Next Article in Journal
The Safety and Efficacy of Tranexamic Acid in Oncology Patients Undergoing Endoprosthetic Reconstruction and a ROTEM-Based Evaluation of Their Hemostatic Profile: A Pilot Study
Next Article in Special Issue
PI3K/Akt Pathway: The Indestructible Role of a Vintage Target as a Support to the Most Recent Immunotherapeutic Approaches
Previous Article in Journal
Combination Treatment of Topical Imiquimod Plus Anti-PD-1 Antibody Exerts Significantly Potent Antitumor Effect
Previous Article in Special Issue
Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 13
Issue 16
10.3390/cancers13163949
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review

by
Federica Rascio
1,*,
Federica Spadaccino
2,
Maria Teresa Rocchetti
3,
Giuseppe Castellano
1,
Giovanni Stallone
1,
Giuseppe Stefano Netti
2 and
Elena Ranieri
2
1
Nephrology Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
2
Clinical Pathology Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
3
Cell Biology Unit, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
*
Author to whom correspondence should be addressed.
Cancers 2021, 13(16), 3949; https://doi.org/10.3390/cancers13163949
Submission received: 30 June 2021 / Accepted: 30 July 2021 / Published: 5 August 2021
(This article belongs to the Special Issue Targeting PI3K Signaling in Cancer)
Browse Figure
Review Reports Versions Notes

Abstract

:

Simple Summary

Drug resistance remains one of the major problems in cancer therapy and is responsible for up to 90% of cancer-related deaths. It exists across all types of cancer and treatment; thus, determining how to overcome this problem is a goal that involves understanding biological mechanisms and also includes clinical trials to test new therapeutic strategies. In this review, we will highlight the emerging role of the PI3K/Akt pathway in drug resistance by discussing recent findings of a multi-level deregulation. Combinational and personalized therapies, which should take this pathway into consideration, might provide better treatment strategies and improved efficacy for fighting drug resistance in cancer.

Abstract

The PI3K/AKT pathway is one of the most frequently over-activated intracellular pathways in several human cancers. This pathway, acting on different downstream target proteins, contributes to the carcinogenesis, proliferation, invasion, and metastasis of tumour cells. A multi-level impairment, involving mutation and genetic alteration, aberrant regulation of miRNAs sequences, and abnormal phosphorylation of cascade factors, has been found in multiple cancer types. The deregulation of this pathway counteracts common therapeutic strategies and contributes to multidrug resistance. In this review, we underline the involvement of this pathway in patho-physiological cell survival mechanisms, emphasizing its key role in the development of drug resistance. We also provide an overview of the potential inhibition strategies currently available.

1. Introduction

In the last few years, the lack of success of therapeutic approaches for cancer, mainly caused by intrinsic or acquired drug resistance, underlines the importance of the investigation of the underlying molecular mechanisms and potential therapeutic targets associated with the progress of tumours [1]. The phosphatidylinositol-3-kinase PI3K/Akt/mammalian target of the rapamycin (mTOR) pathway is one of the most frequently activated intracellular pathways, which is commonly involved as a balancer for human cancer [2]. This pathway is involved in the regulation of multiple cellular physiological processes, particularly cell proliferation, cell cycle, and apoptosis [3]. Several studies have indicated that the occurrence and development of different type of cancers, especially solid ones, depend at least partly on the PI3K/Akt pathway’s deregulation. Thus, enormous effort has been made to find new drugs targeting PI3K/AKT signalling, downstream or upstream of the pathway [4,5,6].
Undoubtedly, the oncogenic variations of the PI3K pathway may be involved in the resistance to specific antineoplastic therapies, including chemotherapies [7]. The abnormal activation of the PI3K/AKT pathway, along with up- or downstream targets transduction, plays a crucial role as an important signalling pathway in charge of drug resistance in many types of neoplasia [8].
The principal post-transcriptional regulators of human genes are microRNAs (miRNAs), small non-coding RNAs which act as direct or indirect modulators of cellular processes, including cell proliferation, differentiation, apoptosis, and invasion [9]. Indeed, even the PI3K/Akt pathway, which plays a key role in carcinogenic processes, is heavily regulated by miRNAs [10].
In this review, we have summed up the aberrant activation of the PI3K/Aky pathway as a link between the multidrug resistance (MDR) and dysfunction of miRNAs that act by dysregulating this signalling pathway. Furthermore, the role of this pathway and miRNAs in target therapies against cancers are discussed.

2. Structure, Activation, and Function of the PI3K/Akt Cascade

PI3K/Akt signalling is an important pathway formed by two parts: phosphatidylinositol-3-kinase (PI3K) and a serine/threonine protein kinase B (PKB) [11].
The phosphoinositide 3-kinases (PI3Ks) are an important family of lipid enzymes which are triggered by phosphorylation of the 3-idroxyl group of phosphatidylinositol on the plasma membrane [2]. There are four different classes of PI3K according to their affinity for lipid substrates and specific structures controlling different aspects of cell biology. Among them, class I PI3K, which includes heterodimeric enzymes composed by a regulatory subunit p85 and a catalytic subunit p110, is the most thoroughly studied isoform in the cancer scenario [12].
Mutations that occur in oncogenes, such as PI3KCA gene encoding the subunit p110, and in tumour suppressor genes, such as phosphatase and tensin homolog (PTEN), are the major mutations responsible for the dysregulation of this pathway in human tumours [13,14].
Generally speaking, PI3K is activated by extracellular signals, such as growth factors, cytokines, and hormones.
In particular, the binding of epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), and insulin-like growth factor I receptor (IGF-IR) to the N-terminal extracellular domain of the transmembrane receptor tyrosine kinase (RTK) causes the auto-phosphorylation of tyrosine residues in the cytoplasmic region of the receptor. This event is responsible for the recruitment and activation of PI3K [15,16].
In addition, PI3K may be directly or indirectly triggered by small Ras-related GTPases, well known for their involvement in carcinogenesis.
RAS is one of the major oncogenes in human cancers, and PI3K is believed to be its main effector. Interacting with different isoforms of class I PI3Ks, RAS binds to and activates p110γ catalytic subunit, leading to an increase in PI3K activity. PI3K/RAS interaction has been shown to be indispensable for maintaining cancer cell survival and proliferation [17].
Class I PI3Ks, a protein heterodimer composed of two different proteins, a regulatory and a catalytic subunit, are also divided into two categories, IA and IB subsets, on sequence similarity. Particularly, class IA PI3K binds, with its regulatory subunit, the tyrosine receptors on cell membrane stimulated by ligands and determines the activation of the catalytic subunit that converts PIP2 to the second messenger PIP3 [18,19,20].
The most significant downstream effector of PI3K is the serine/threonine kinase Akt, which plays a crucial role in the signal transduction of the entire signalling cascade [21]. Akt1, Akt2, and Akt3 are three different isoforms of Akt in mammals, which are activated in an isoform-specific manner by many signals, including cytokine receptors, integrins, and B and T cell receptors [22,23]. Akt activation depends on the phosphorylation of both the internal catalytic domain and regulatory domain, but its stabilization requires the phosphorylation of other multiples sites. Subsequently to activation, Akt transfers from the cell membrane to other cell regions to phosphorylate and initiate downstream effector molecules [24].
There are several Akt target proteins; most of are transcription factors which may induce, if mutated, alterations in cancer cells function and metabolism. Among these, glycogen synthase kinase 3 (GSK3) is inhibited in response to growth factors via AKT-mediated phosphorylation, leading to ubiquitylation and proteasomal degradation of its targets involved in cellular metabolism [25].
AKT phosphorylation induces cancer development and progression by inhibiting members of the FOXO family of transcription factors (FOXO1, FOXO3A, FOXO4), which are physiologically involved in the suppression of growth and proliferation [26].
The main target of PI3K/Akt is the serine/threonine kinase mTOR. mTOR includes mTOR complex 1 (mTORC1), whose components are mTOR, Raptor, and mLST8 subunits, and mTOR complex 2 (mTORC2), which consists of mTOR, Rictor, Sin1, and mLST1 [27,28]. Akt induces the phosphorylation and inhibition of the tuberous sclerosis complex 2 (TSC2) protein which, in turn, inhibits Ras homologue enriched in brain (RHEB) and causes mTORC1 activation. Thus, the mTORC1 complex is part of the PI3K/Akt/mTOR pathway as a downstream molecule which promotes cell growth, protein synthesis, and energy storage [28].
This complex is stimulated by the presence of nutrients and depends on the energetic status for its activity. On the contrary, in conditions of starvation, mTORC1 is inhibited and may contribute to an increased apoptosis [29]. Undoubtedly, when mTORC1 is inhibited, autophagy is induced by AMPK, which causes the creation of energy for the survival of cells [30].
The phosphorylation of mTOR is considered a specific marker for tumour progression and, in turn, mediates the activation of downstream target factors, such as S6K and 4E-BP1. In particular, phosphorylated 4E-BP1 (p4E-BP1) is associated with a greater risk of progression in many neoplasms and correlates with aggressive pathologic grade and poor prognosis [31,32,33,34].

3. Altered PI3K/Akt Signalling Pathway: Its Pathogenic Role in Human Cancer

The PI3K/Akt/mTOR pathway cascade is frequently disrupted, more often over-activated, in different human malignant cases [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35]. Indeed, more and more evidence has demonstrated that the hyper-activation of the PI3K/Akt pathway contributes to the carcinogenesis, proliferation, invasion, metastasis, and drug resistance of tumour cells [5]. Among the various genetic factors involved in the molecular mechanisms of human cancer, such as P53, NFKB, STAT3, or Myc, the PI3K/Akt axis receives major attention, justified by its central role in multiple cellular processes.
The PI3K/Akt/mTOR pathway is not only involved in the regulation of the proliferation and apoptosis of cancer cells but also promotes normal and tumour angiogenesis [36].
Genetic alterations have been identified in every level of the PI3K/Akt signalling cascade. The phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), also called p110 alpha protein, is a class I PI3K catalytic subunit that, at first, was considered to be highly involved in ovarian cancers, playing a role as an oncogene [37], however, the somatic mutations of PIK3CA have also been detected in colorectal, glioblastoma, gastric, breast, lung, and kidney cancers [38,39,40]. Similarly, recurring mutations of PIK3R1 gene coding, in detail for the p85 regulatory subunit, have also been detected in endometrial, glioblastoma, uterine carcinosarcoma, and bladder urothelial carcinoma [41].
The hyper-activation of the PI3K/Akt pathway, caused by mutations of PI3K family genes, determines the poor prognosis in cancers of the brain and of the central nervous system [42,43,44]; the knockdown of the same genes significantly inhibits the invasion of tumours through the hypo-activation of Akt [45]. Aberrant activation of PI3K/Akt signalling in the cancer of the endocrine system is caused by the same genetic mutations.
The second most mutated or deleted tumour suppressor after p53, across all cancers, is the phosphatase and tensin homolog deleted on chromosome 10 (PTEN), the lipid phosphatase that counteracts the PI3K pathway. It is well known that PTEN negatively regulates PI3K/AKT acting as a tumour suppressor by dephosphorylating PIP3, and its function loss leads to an increase in PI3K/AKT pathway activity. As a consequence, PTEN alterations, mutations, and deletions can induce tumorigenesis and other diseases [46,47].
In terms of Akt, the main member of the PI3K/Akt pathway, regulating the effector targets by phosphorylation, many alterations have been suggested in cancer scenario. First of all, the over-expression of Akt2 isoform has already been suggested not only in ovarian cancers but also in several other solid organ neoplasias [48,49]. In addition, more evidence has indicated that Akt2 and Akt3 isoforms are more frequently amplified than Akt1 in cancer disorders [50].
In addition, lipid and protein phosphatases controlling Akt activity are frequently downregulated in human cancer determining the overexpression of phosphorylated Akt, such as inositol polyphosphate 4-phosphatase (INPP4), which catalyses the dephosphorylation of PI (3,4)P2 to PI(3)P at the plasma membrane and on endomembranes, leading, if it is reduced, to the subsequent increase of PI3K/Akt pathway activity [8,51]. Activated Akt produces eNOS allocation in the vascular endothelium, which culminates in angiogenesis and improves the transcriptional activity of NF-kappa B, thus promoting and supporting the proliferation of tumours [52,53,54]. Consequently, when growth factors boost and activate PI3K, its effector Akt further activates downstream molecules and regulates the proliferation, invasion, metastasis, and angiogenesis of cancer cells.
At the layer downstream of Akt, the most common deregulated mechanisms involve the effector target mTOR, responsible for tumour growth progression, as in endometrial malignancies [55,56,57]. On the other hand, it has been demonstrated that the inhibition of mTOR drastically reduces the progression of endometrial cancer [58].
In ovarian cancer, the PI3K/Akt signalling pathway is dysregulated due to mutations in PI3K, PI3KCA, and PTEN deletion, in the regulatory and catalytic domains, or due to modifications of downstream targets of PI3K [59,60,61,62]. Thus, it is clear that the dysregulation of the whole pathway, at multiple layers, rather than individual genes is required to induce tumour progression and altered phenotype in gynaecological cancer disorders [59]. Nevertheless, it has been clarified that PI3KCA mutations exclude alterations in other components of the pathway, with the exception of endometrial or bowel cancers, where a multi-level impairment of the entire pathway is frequently involved [63,64]. In renal clear cell carcinoma (RCC), cancer classified as highly resistant to traditional treatments such as chemotherapies or radiotherapies, the discovery of new diagnostic or prognostic biomarkers has been potentially fruitful and, in part, explored [65,66]. With regard to the PI3K/Akt pathway, although the mutations affecting its components are limited, the downstream effect is a constitutive activation of the cascade [67]. Genetic mutations in its members are frequently observed in RCC, which exacerbate the hyper-activation of the PI3K/Akt/mTOR signalling pathway. However, in patients with clear cell RCC, the mRNA level of the expression of the principal molecules involved in the pathway demonstrate no significant differences if compared to normal tissues, suggesting that the activation of the cascade may not depend on their transcriptional regulation [59]. This evidence indicates that the pathway activity in RCC not only depends on the mRNA and protein expression levels, but it also relies on protein activation through phosphorylation, as demonstrated by the function of phosphor-mTOR and phosphor-Akt. In conditions of deprivation of glucose, multiple cell lines show a unique form of Akt phosphorylation on Thr308, which represents a central Akt activation mechanism in RCC (Figure 1) [67,68].

4. miRNAs’ Regulation on the PI3K/Akt Pathway

Cancer is the result of an intricate interaction of genetic and environmental factors. Recent studies have evidenced the encoding of microRNAs (miRNAs) as participants in the pathogenesis of cancer, emerging as a new class of important regulators of the PI3K/AKT pathway [69,70]. These small-size RNA molecules regulate the expression of target genes by binding with their 3′ untranslated regions or, alternatively, with 5′ untranslated regions [71,72,73]. The altered expression of miRNAs in cancer cells works by de-regulating the expression of genes related to apoptosis or autophagy that play a central role in the mechanisms of action of drug resistance [74]. As a consequence, it is well known that miRNAs are potential modulators in the initiation and progression of various disorders. Numerous studies investigating the regulation of miRNAs on the PI3K/Akt pathway are summarised in Table 1. For instance, in RCC cancer, miR-182-5p has been shown to be a negative regulator of Akt, so that its upregulation results in Akt inhibition and a subsequent slowing down of cancer cell proliferation [75]. On the other hand, miR-122 has been demonstrated to be a positive modulator of the pathway [76]. Finally, miR-205-5p as well as miR-182-5p functions as a negative regulator by targeting VEGFA and the PI3K/Akt signalling pathway [77].
In gastric cancer, dysregulated miRNAs have been identified as being partly responsible for malignant processes, including drug resistance, depending on the aberrantly activated PI3K pathway, normally controlled by miRNAs [78]. Indeed, in the gastric system, the constitutive activation of this pathway that promotes cancer is due to epigenetic or genetic alterations regarding the components of this cascade [79,80]. However, in addition to genetic modifications, the onset of cancer depends on the oncogenic effects of dysregulated miRNAs and on the altered activation of their mediators, the PTEN/PI3K/Akt pathway included [81,82]. Interestingly, it was observed that miR-196b promotes gastric cancer by stimulating the pathway activation, while the expression of tumour-suppressor miRNAs (miR137, miR-34, miR203, miR15a miR16, and miR375) exert their effects by targeting Akt2 [83,84,85,86,87,88,89].
Other proteins of the pathway, including PIK3CB and mTOR, are inhibited by miR125b-2, miR-451a, and miR101-2 [90]. Based on these forms of evidence, the potential applications of miRNAs for drugs, including miRNA mimics and inhibitors, in combination with PI3K/AKT pathway inhibitor has been well documented in the treatment of gastric cancer [9].
In bladder cancer, the expression of several oncomiRNAs, microRNAs that have been associated with specific cancer forming events, has been indicated in tissue, blood, and urine samples. These dysregulated miRNAs have an influence on several biological elements and signalling pathways, including PI3K/Akt [71,91,92]. The involvement of miRNAs in bladder cancer disorders shows that miRNAs may be considered as potential therapeutic targets to contrast multidrug resistant situations [93].
Numerous studies have shown that changes in miR27a3p expression are associated with chemoresistance not only in bladder, gastric, and ovarian carcinoma but also in leukaemia, hepatocellular cancer, and breast cancer through the PI3K/Akt signalling pathway [94,95,96,97,98]. In particular, new evidence suggests that miR520h is responsible for breast cancer cell resistance to paclitaxel by attenuating the stability of the tumour suppressor PTEN and by activating the Akt pathway [99].
In the whole, these findings indicate a new starting point to overcome drug resistance based on strategies that target the implicated miRNAs.
Table
Table 1. The regulation of miRNAs on the PI3K/Akt pathway throughout different protein targets.
Table 1. The regulation of miRNAs on the PI3K/Akt pathway throughout different protein targets.
StudymiRNATumour TypeRegulationTargetEffect
Xu X et al. [75]miR-182-5pRCCNegativeAKT/FOXO3a via FLOT1Cancer proliferation
Lian JH et al. [76]miR-122PositivePI3K/AKTCancer proliferation
Huang J et al. [69]miR-205-5pNegativePI3K/Akt/mTOR and VEGFATumour suppression
Yang SM et al. [81]miR-21GastricNegativePTEN/PI3K/AktDrug resistance
Li NA et al. [83]miR-196bPositivePI3K/Akt/mTORTumour promoting
Tsukamoto Y et al. [84]miR-375NegativePKD1/Akt and 14-3-3zetaTumour suppression
Peng Y et al. [85]miR-34NegativePDGFR/Akt and METTumour suppressor
Wang T et al. [86]miR15a, miR16NegativeTWIST1Tumour suppressor
Kang W et al. [87]YAP1
Wu L et al. [88]miR137NegativeAKT2Tumour suppressor
Liang M et al. [89]miR203NegativePIK3CA/AktTumour suppressor
Riquelme I et al. [90]miR125b-2, miR-451a and miR101-2NegativemTOR via PIK3CB and TSC1Tumour suppressor
Deng Y et al. [91]miR27aBladderNegativeRUNX-1Drug resistance
Zhao X et al. [94]gastric,Negativep21
Li Z et al. [95]ovarianNegativeHIPK2
Feng DD et al. [96]leukaemiaPositiveMDR1
Chen Z et al. [97]hepaticPositiveFZD7/β-catenin
Zhu B et al. [98]breastPositiveBTG2
Geng W et al. [99]miR-520hBreastPositiveOTUD3/PTEN
RCC: renal cell carcinoma; FLOT1: flotillin-1; FOXO3a: (Forkhead Transcription Factor O Subfamily Member 3a); PTEN: phosphatase and tension homolog deleted on chromosome 10; PKD1: polycystic kidney disease 1; PDGFR: platelet-derived growth factor receptor; MET: tyrosine-protein kinase Met; TWIST1: oncoprotein with important roles in the epithelial to mesenchymal transition process; YAP1: Yes-associated protein 1; PIK3CA: enzymatic subunit p110α of phosphatidylinositol 3-kinase; TSC1: tuberous sclerosis complex 1; RUNX-1: runt-related transcription factor 1; HIPK2: homeodomain-interacting protein kinase-2; MDR1: multiple drug resistance protein 1 gene; FZD7: frizzled class receptor 7; BTG2: B-cell translocation gene 2.

5. Inhibition of the PI3K/Akt Pathway

The PI3K/Akt/mTOR pathway is activated by many factors targeting different members of the pathway [95]. The primary negative regulator of this pathway is the tumour suppressor PTEN; it has lipid and protein phosphatase activity by inhibiting PI3 phosphorylation and catalysing the reaction opposite to PIP3 generation, the conversion of PIP3 to PIP2 [100,101]. In fact, PIP3 levels are significantly increased in PTEN-knockout mice compared to wild mice, and Akt is constantly activated [102]. PTEN is able to interfere with the accumulation of Akt in the cell membrane and leads to the release of inactive Akt to the cytoplasm, thus acting downstream of the Akt pathway [103]. The phosphorylation of one of its phosphorylation sites at the c-terminal tail allows PTEN to attain a closed state, thereby determining the protein stability and consequent inactivation; on the contrary, its dephosphorylating contributes to an increase in activity [104]. Other phosphatases, apart from PTEN, are responsible for the termination of the transduction signalling, at downstream level of PI3Ks. Among them, the family of Src-homology 2-containing inositol 5′-phosphatase phosphatases (SHIP) plays a fundamental role in the negative regulation of Akt [105,106].
Many drugs, like PI3K inhibitors, targeting single or more proteins, include LY294002, which operates by inactivating PKB and determining cell cycle arrest. In addition, a new generation of PI3K inhibitors in preclinical studies may induce apoptosis and have so far been well tolerated in the early stages of clinical trials [107,108,109].
Among Akt inhibitors, more evidence has encouraged the clinical application of Palomid529 and perifosine, both of which enhance the radio-sensitivity of tumour cells [110,111]. Furthermore, mTOR is a sensitive target for rapamycin and seems to be the most qualified target belonging to PI3K/Akt pathway. Classically, rapamycin has been used as an immunosuppressant agent to prevent organ transplant rejection, but now it is also being employed as a tumour suppressor against mTOR [112,113]. Clinical results obtained from mTOR inhibitors support oncologists in actively developing these drugs [114]; a brand new rapamycin, everolimus, selectively inhibits mTORC1 and preserves mTORC2 [115]. New emerging therapeutic strategies based on dual PI3K/Akt/mTOR inhibitors are able to block mTOR as well as PI3K and Akt activation maintaining a good tolerance in the clinical trials. In this way, the pathway is inhibited at different layers in order to increase the efficiency of new combination therapies [116].

6. The PI3K/AKT Pathway and Drug Resistance

PI3K signalling and its downstream effecter Akt are considered significant causes of chemoresistance in cancer therapy in a variety of tumours [117,118,119,120,121,122]. Abnormal initiation of the pathway inhibits chemotherapeutic-induced apoptosis by multiple mechanisms, such as reinforcing the action of anti-apoptotic genes and counteracting the pro-apoptotic genes [123]. Bcl-2 proteins, located on the mitochondrial membrane, include anti-apoptotic proteins, such as BCL-xl and Bcl-2, and pro-apoptotic proteins, such as Bax and Bad [124,125]. Activated Akt stimulates PAK1, which, in turn, phosphorylates Bad, causing its release from the mitochondrial membrane to the cytoplasm and, at the same time, inhibits the translocation of Bax from the cytoplasm to the mitochondria. Therefore, the hyper-activation of Akt promotes cell survival via the stimulation of Bcl-2 and via the inhibition of Bax, which are in charge of cancer cell resistance.
Bcl-2 acts as an oncoprotein, and its overexpression correlates to multidrug resistance (MDR). Since cancer cells exploit Bcl-2 to evade apoptosis, it appears that in many tumours there is a selection of Bcl-2-dependent cells [126,127]. Although the overexpression of Bcl-2 predisposes to tumour invasiveness, some studies have reported that it may represent a crucial target for Bcl-2 inhibitors and, therefore, a good prognostic factor in patients with different types of cancer [128,129,130].
An abnormal change in the pathway also induces the upregulation of X-linked inhibitor of apoptosis (Xiap), a downstream effector of Akt which prevents apoptosis in several ways, one of which is the inhibition of autophagy via regulation of the cytosolic level of p53 [131]. Normally, phosphor-Xiap interacts with Mdm2 and mediates its rapid degradation, thereby maintaining the relatively high levels of cytosolic p53. Under stress conditions, the Akt inhibition determines the dephosphorylation of Xiap, thus promoting dissociation from Mdm2. This makes Mdm2 stable and, as a consequence, leads to the fast degradation of p53, facilitating at the same time the induction of autophagy [131].
XIAP belongs to the IAP family and plays a crucial role in inhibiting caspase-3, caspase-7, or caspase-9 [75]. IAPs were found to be over-expressed in many cancer types and to be related to tumour cell survival, leading to poor prognosis and overall survival [132,133,134,135,136,137].
For this reason, the use of Xiap inhibitors, alone or in combination with PI3-kinase inhibitors, is considered to be a potential therapeutic strategy for the management of cancer [137,138,139].
The inhibition of apoptosis and the advancement of tumour growth may be due to the over-activation of the NF-kB system generated by the triggering of PI3K/Akt [140,141]; as result, NF-kB is able to accelerate the cell cycle process in tumour cells, contributing to the development of multidrug-resistance [142,143].
The activation of PI3K/Akt signalling inactivates FOX factors, which are involved in numerous physiological processes, including cell division, cell death, cell invasion, and drug resistance [144].
It has been reported that the over-expression of Akt1 by the activation of HER2/PI-3K confers a broad-spectrum chemoresistance on breast cancer cells [145]. Likewise, the hyper-expression of paired-related nomeobox-1 (PRRX1) determined by the activation of PTEN/PI3K/AKT signalling leads to the epithelial-to-mesenchymal transition (EMT) implicated in multiple processes, such as cell invasion and MDR in breast cancer [146].
In addition, as explained above, the dysregulation of micro-RNA that exerts effects on the PI3K pathway may also exacerbate multidrug resistance in cancer cells. These miRNAs could regulate MDR through targeting a specific gene or targeting several genes simultaneously, including genes affecting the response of cells to chemotherapy drugs. One miRNA can target different messenger RNAs (mRNAs), and, on the other hand, one mRNA can be regulated by many miRNAs. Given the complexity and heterogeneity of tumour cells, the effects exerted by miRNAs on drug resistance depends on the different kinds of tumours and differ from tumour to tumour [147].

7. Target Therapies and Future Prospective

In the previous sections, we have analysed the principal alterations occurring in the PI3K/Akt pathway in human malignancies. Given that this cascade is considered the most frequently activated pathway in standard cancers, its members represent future targets for anti-cancer drugs, including nearly isoform-specific PI3K inhibitors, dual inhibitors, mTOR and Akt inhibitors, and miRNA inhibitors [148].
In recent years, targeted drugs for each molecular site and domain involved in different tumours have gained further development and validation. Thus, it is reasonable to think that with the continuous exploration of the underlying mechanisms, the discovery of more promising drug targets is becoming the best therapeutic approach for cancer treatment and prevention. With the purpose of enhancing the sensitivity of tumour cells, PI3K/Akt inhibitors have been recently tested with success [149]. For instance, in breast cancer, the introduction of PI3K/Akt inhibitors such as a novel drug, econazole, has been able to counter the activation of PI3K/Akt pathway and, in turn, to prevent the resistance of tumour cells by exerting cytotoxic activity [150]; the treatment with phenybutyl isoselenocyanate (ISC-4) considerably slows down the activation of PI3K/Akt in a dose-dependent way [151]. Consequently, the use of specific inhibitors of this signalling pathway, alone or in combination, is currently under evaluation, for the development of brand new strategies in order to counter the drug resistance of various cancers.
In many cases, the therapeutic resistance emerges as a consequence of several mechanisms that contrast the suppression of the signalling pathway and cause, as a form of compensation, the activation of other signalling pathways. Thus, clinical or preclinical trials are starting to determine the efficiency of various combination therapies to address different levels of inhibitors pathways.
As previously mentioned, IAPs are emerging as promising targets for cancer therapy, and several clinical trials based on IAPs antagonist are currently under evaluation [152].
The implication of changes in the miRNA expression profile may lead to an increase of PI3K/Akt/mTORC1 activity that perpetuates and exacerbates the multidrug resistance in cancer. The miRNAs and their intricate networks have arisen as fundamental biological elements with a high potential for clinical application. As a matter of fact, different strategies to improve miRNAs delivery have been performed on the basis of their modulation in cancer cells [153]. Although it is expected that specific inhibitors of miRNAs can reduce the multidrug resistance of cancers via deregulation of the PI3K/Akt pathway, at present, no therapy targeting specific miRNAs has been performed in medical practice, and further studies are required.

8. Conclusions

Significant progress has been recently made in the management of cancer drug-resistance. The new challenge is to overcome the limitations of the classical therapeutic strategies, which may be met with the introduction of novel agents inhibiting not only PI3K/Akt targets but other members of the same pathway. The correct combination of available drugs and the discovery of new potential biomarkers, such as miRNAs, are needed and warranted.

Author Contributions

Conceptualization, writing, and original draft preparation: F.R. and F.S.; writing review, visualization, and data curation: M.T.R.; funding acquisition: F.R., G.C., and G.S.; writing review and editing: G.S.N.; supervision and writing review: E.R. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Italian Ministry of Education and University (MIUR) (Giovani Ricercatori GR-2016-02362239, granted to F.R., 2016) and by the Department of Medical and Surgical Sciences, University of Foggia (PRA 2019, granted to G.S.N.).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Ke, X.; Shen, L. Molecular targeted therapy of cancer: The progress and future prospect. Front. Lab. Med. 2017, 1, 69–75. [Google Scholar] [CrossRef]
  2. Shi, X.; Wang, J.; Lei, Y.; Cong, C.; Tan, D.; Zhou, X. Research progress on the PI3K/AKT signaling pathway in gynecological cancer (Review). Mol. Med. Rep. 2019, 19, 4529–4535. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Barra, F.; Evangelisti, G.; Ferro, D.L.; Domenico, S.; Ferraioli, D.; Vellone, V.G.; De Cian, F.; Ferrero, S. Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer. Expert Opin. Investig. Drugs 2019, 28, 131–142. [Google Scholar] [CrossRef] [PubMed]
  4. Iida, M.; Harari, P.M.; Wheler, D.L.; Toulany, M. Targeting AKT/PKB to improve treatment outocomes for solid tumors. Mutat. Res./Fundam. Mol. Mech. Mutagen. 2020, 819–820, 111690. [Google Scholar] [CrossRef] [PubMed]
  5. Jiang, N.; Dai, Q.; Su, X.; Fu, J.; Feng, X.; Peng, J. Role of PI3K/AKT pathway in cancer: The framework of malignant behavior. Mol. Biol. Rep. 2020, 47, 4587–4629. [Google Scholar] [CrossRef]
  6. Shorning, B.; Dass, M.S.; Smalley, M.J.; Pearson, H.B. The PI3K/AKT-mTOR Pathway and prostate cancer: At the crossroads of AR, MAPK, and WNT signaling. Int. J. Mol. Sci. 2020, 21, 4507. [Google Scholar] [CrossRef] [PubMed]
  7. Martini, M.; De Santis, M.C.; Braccini, L.; Gulluni, F.; Hirsch, E. PI3K/AKT signaling pathway and cancer: An update review. Ann. Med. 2014, 46, 372–383. [Google Scholar] [CrossRef]
  8. Liu, R.; Chen, Y.; Liu, G.; Li, C.; Song, Y.; Cao, Z.; Li, W.; Hu, J.; Lu, C.; Liu, Y. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Dis. 2020, 11, 797. [Google Scholar] [CrossRef]
  9. Hu, M.; Zhu, S.; Xiong, S.; Xue, X.; Zhou, X. MicroRNAs and the PTEN/PI3K/Akt pathway in gastric cancer (Review). Oncol. Rep. 2019, 41, 1439–1454. [Google Scholar] [CrossRef] [Green Version]
  10. Paladini, L.; Fabris, L.; Bottai, G.; Raschioni, C.; Calin, G.A.; Santarpia, L. Targeting microRNA sas key modulators of tumor immune response. Exp. Clin. Cancer Res. 2016, 35, 103. [Google Scholar] [CrossRef] [Green Version]
  11. Xu, F.; Na, L.; Li, Y.; Chen, L. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumors. Cell Biosci. 2020, 10, 54. [Google Scholar] [CrossRef] [Green Version]
  12. Vanhaesebroeck, B.; Guillermet-Guibert, J.; Graupera, M.; Bilanges, B. The emerging mechanisms of isoform-specific PI3K signalling. Nat. Rev. Mol. Cell Biol. 2010, 11, 329–341. [Google Scholar] [CrossRef]
  13. Samuels, Y.; Ericson, K. Oncogenic PI3K and its role in cancer. Curr. Opin. Oncol. 2006, 18, 77–82. [Google Scholar] [CrossRef] [PubMed]
  14. Song, M.S.; Salmena, L.; Pandolfi, P.P. The functions and regulation of the PTEN tumour suppressor. Nature reviews. Mol. Cell Biol. 2012, 13, 283–296. [Google Scholar]
  15. Fruman, D.A.; Rommel, C. PI3K and cancer: Lessons, challenges and opportunities. Nat. Rev. Drug Discov. 2014, 13, 140–156. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Osaki, M.; Oshimura, M.; Ito, H. PI3K-Akt pathway: Its functions and alterations in human cancer. Apoptosis 2004, 9, 667–676. [Google Scholar] [CrossRef]
  17. Castellano, E.; Downward, J. RAS Interaction with PI3K more than Just another Effector Pathway. Genes Cancer 2011, 2, 261–274. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Yu, X.; Long, Y.C.; Shen, H.M. Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy. Autophagy 2015, 11, 1711–1728. [Google Scholar] [CrossRef] [Green Version]
  19. Ghigo, A.; Morello, F.; Perino, A.; Hirsch, E. Phosphoinositide 3-kinases in health and disease. Sub-Cell. Biochem. 2012, 58, 183–213. [Google Scholar]
  20. Williams, R.; Berndt, A.; Miller, S.; Hon, W.C.; Zhang, X. Form and fexibility in phosphoinositide 3-kinases. Biochem. Soc. Trans. 2009, 37, 615–626. [Google Scholar] [CrossRef] [Green Version]
  21. Szymonowicz, K.; Oeck, S.; Malewicz, N.M.; Jendrossek, V. New insights into protein kinase B/Akt signaling: Role of localized Akt activation and compartment-specific target proteins for the cellular radiation response. Cancers 2018, 10, 78. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Toulany, M.; Maier, J.; Iida, M.; Rebholz, S.; Holler, M.; Grottke, A.; Jüker, M.; Wheeler, D.L.; Rothbauer, U.; Rodemann, H.P. Akt1 and Akt3 but not Akt2 through interaction with DNA-PKcs stimulate proliferation and post-irradiation cell survival of K-RAS-mutated cancer cells. Cell Death Discov. 2017, 3, 17072. [Google Scholar] [CrossRef]
  23. Girardi, C.; James, P.; Zanin, S.; Pinna, L.A.; Ruzzene, M. Differential phosphorylation of Akt1 and Akt2 by protein kinase CK2 may account for isoform specific functions. Biochim. Biophys. Acta 2014, 1843, 1865–1874. [Google Scholar] [CrossRef]
  24. Andjelković, M.; Alessi, D.R.; Meier, R.; Fernandez, A.; Lamb, N.J.; Frech, M.; Cron, P.; Cohen, P.; Lucocq, J.M.; Hemmings, B.A. Role of translocation in the activation and function of protein kinase B. J. Biol. Chem. 1997, 272, 31515–31524. [Google Scholar] [CrossRef] [Green Version]
  25. Frame, S.; Cohen, P.; Biondi, R.M. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol. Cell 2001, 7, 1321–1327. [Google Scholar] [CrossRef]
  26. Hornsveld, M.; Dansen, T.B.; Derksen, P.W.; Burgering, B.M.T. Re-evaluating the role of FOXOs in cancer. Semin. Cancer Biol. 2018, 50, 90–100. [Google Scholar] [CrossRef]
  27. Murugan, A.K. mTOR: Role in cancer, metastasis and drug resistance. Semin. Cancer Biol. 2019, 9, 92–111. [Google Scholar] [CrossRef] [PubMed]
  28. Kim, J.; Guan, K.L. mTOR as a central hub of nutrient signalling and cell growth. Nat. Cell Biol. 2019, 21, 63–71. [Google Scholar] [CrossRef]
  29. Carroll, B.; Dunlop, E.A. The lysosome: A crucial hub for AMPK and mTORC1 signalling. Biochem. J. 2017, 474, 1453–1466. [Google Scholar] [CrossRef] [Green Version]
  30. Tapia, O.; Riquelme, I.; Leal, P.; Sandoval, A.; Aedo, S.; Weber, H.; Letelier, P.; Bellolio, E.; Villaseca, M.; Garcia, P.; et al. The PI3K/AKT/mTOR pathway is activated in gastric cancer with potential prognostic and predictive significance. Virchows Arch. 2014, 465, 25–33. [Google Scholar] [CrossRef] [PubMed]
  31. Campbell, L.; Jasani, B.; Griffiths, D.F.; Gumbleton, M. Phospho-4e-BP1 and eIF4E overexpression synergistically drives disease progression in clinically confined clear cell renal cell carcinoma. Am. J. Cancer Res. 2015, 5, 2838–2848. [Google Scholar] [PubMed]
  32. Benavente, S.; Vergés, R.; Hermosilla, E.; Fumana, V.; Casanova, N.; García, A.; Ramón y Cajal, S.; Giralt, J. Overexpression of phosphorylated 4E-BP1 predicts for tumor recurrence and reduced survival in cervical carcinoma treated with postoperative radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 2009, 75, 1316–1322. [Google Scholar] [CrossRef] [PubMed]
  33. Korkolopoulou, P.; Levidou, G.; El-Habr, E.A.; Piperi, C.; Adamopoulos, C.; Samaras, V.; Boviatsis, E.; Thymara, I.; Trigka, E.A.; Sakellariou, S.; et al. Phosphorylated 4E-binding protein 1 (p-4E-BP1): A novel prognostic marker in human astrocytomas. Histopathology 2012, 61, 293–305. [Google Scholar] [CrossRef]
  34. Karlsson, E.; Pérez-Tenorio, G.; Amin, R.; Bostner, J.; Skoog, L.; Fornander, T.; Sgroi, D.C.; Nordenskjöld, B.; Hallbeck, A.L.; Stål, O. The mTOR effectors 4EBP1 and S6K2 are frequently coexpressed, and associated with a poor prognosis and endocrine resistance in breast cancer: A retrospective study including patients from the randomised Stockholm tamoxifen trials. Breast Cancer Res. 2013, 15, R96. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Stallone, G.; Infante, B.; Prisciandaro, C.; Grandaliano, G. mTOR and Aging: An Old Fashioned Dress. Int. J. Mol. Sci. 2019, 20, 2774. [Google Scholar] [CrossRef] [Green Version]
  36. Zhou, Y.; Li, S.; Li, J.; Wang, D.; Li, Q. Effect of microRNA-135 on cell proliferation, migration, invasion, apoptosis and tumor angiogenesis through the IGF-1/PI3K/Akt signaling pathway in non-small cell lung cancer. Cell. Physiol. Biochem. 2017, 42, 1431–1446. [Google Scholar] [CrossRef]
  37. Shayesteh, L.; Lu, Y.; Kuo, W.-L.; Baldocchi, R.; Godfrey, T.; Collins, C.; Pinkel, D.; Powell, B.; Mills, G.B.; Gray, J.W. PIK3CA is implicated as an oncogene in ovarian cancer. Nat. Genet. 1999, 21, 99–102. [Google Scholar] [CrossRef]
  38. Samuels, Y.; Waldman, T. Oncogenic mutations of PIK3CA in human cancers. Curr. Top. Microbiol. Immunol. 2010, 347, 21–41. [Google Scholar]
  39. Alqahtani, A.; Ayesh, H.S.K.; Halawani, H. PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis. Cancers 2019, 12, 93. [Google Scholar] [CrossRef] [Green Version]
  40. Murph, M.M.; Smith, D.L.; Hennessy, B.; Lu, Y.; Joy, C.; Coombes, K.R.; Mills, G.B. Individualized molecular medicine: Linking functional proteomics to select therapeutics targeting the PI3K pathway for specific patients. Adv. Exp. Med. Biol. 2008, 622, 183–195. [Google Scholar]
  41. Cheung, L.W.T.; Hennessy, B.T.; Li, J.; Yu, S.; Myers, A.P.; Djordjevic, B.; Lu, Y.; Stemke-Hale, K.; Dyer, M.D.; Zhang, F.; et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 2011, 1, 170–185. [Google Scholar] [CrossRef] [Green Version]
  42. Dolecek, T.A.; Propp, J.M.; Stroup, N.E.; Kruchko, C. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro-Oncology 2012, 14, v1–v49. [Google Scholar] [CrossRef]
  43. Zhao, H.F.; Wang, J.; Shao, W.; Wu, C.P.; Chen, Z.P.; To, S.T.; Li, W.P. Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: Current preclinical and clinical development. Mol. Cancer 2017, 16, 100. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Brennan, C.W.; Verhaak, R.G.; McKenna, A.; Campos, B.; Noushmehr, H.; Salama, S.R.; Zheng, S.; Chakravarty, D.; Sanborn, J.Z.; Berman, S.H.; et al. The somatic genomic landscape of glioblastoma. Cell 2013, 155, 462–477. [Google Scholar] [CrossRef]
  45. Weber, G.L.; Parat, M.O.; Binder, Z.A.; Gallia, G.L.; Riggins, G.J. Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells. Oncotarget 2011, 2, 833–849. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Keniry, M.; Parsons, R. The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene 2008, 27, 5477–5485. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Milella, M.; Falcone, I.; Conciatori, F.; Cesta Incani, U.; Del Curatolo, A.; Inzerilli, N.; Nuzzo, C.M.; Vaccaro, V.; Vari, S.; Cognetti, F.; et al. PTEN: Multiple Functions in Human Malignant Tumors. Front. Oncol. 2015, 16, 5–24. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Cheng, J.Q.; Ruggeri, B.; Klein, W.M.; Sonoda, G.; Altomare, D.A.; Watson, D.K.; Testa, J.R. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc. Natl. Acad. Sci. USA. 1996, 93, 3636–3641. [Google Scholar] [CrossRef] [Green Version]
  49. Hers, I.; Vincent, E.E.; Tavaré, J.M. Akt signalling in health and disease. Cell. Signal. 2011, 23, 1515–1527. [Google Scholar] [CrossRef] [PubMed]
  50. Cohen, M.M. The AKT genes and their roles in various disorders. Am. J. Med. Genet. A 2013, 161, 2931–2937. [Google Scholar] [CrossRef]
  51. Siess, K.M.; Leonard, T.A. Lipid-dependent Akt-ivity: Where, when, and how. Biochem. Soc. Trans. 2019, 47, 897–908. [Google Scholar] [CrossRef] [Green Version]
  52. Chang, C.Z.; Wu, S.C.; Chang, C.M.; Lin, C.L.; Kwan, A.L. Arctigenin, a potent ingredient of Arctium lappa L., induces endothelial nitric oxide synthase and attenuates subarachnoid hemorrhage-induced vasospasm through PI3K/Akt pathway in a rat model. BioMed Res. Int. 2015, 2015, 490209. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Chin, Y.R.; Toker, A. The actin-bundling protein palladin is an Akt1-specific substrate that regulates breast cancer cell migration. Mol. Cell. 2010, 38, 333–344. [Google Scholar] [CrossRef] [Green Version]
  54. Jafari, M.; Ghadami, E.; Dadkhah, T.; Akhavan-Niaki, H. PI3k/AKT signaling pathway: Erythropoiesis and beyond. J. Cell. Physiol. 2019, 234, 2373–2385. [Google Scholar] [CrossRef] [PubMed]
  55. Mazloumi Gavgani, F.; Smith Arnesen, V.; Jacobsen, R.G.; Krakstad, C.; Hoivik, E.A.; Lewis, A.E. Class I phosphoinositide 3-Kinase PIK3CA /p110α and PIK3CB/p110β isoforms in endometrial cancer. Int. J. Mol. Sci. 2018, 19, 3931. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Prat, J.; Gallardo, A.; Cuatrecasas, M.; Catasús, L. Endometrial carcinoma: Pathology and genetics. Pathology 2007, 39, 72–87. [Google Scholar] [CrossRef] [PubMed]
  57. Lee, T.Y.; Martinez-Outschoorn, U.E.; Schilder, R.J.; Kim, C.H.; Richard, S.D.; Rosenblum, N.G.; Johnson, J.M. Metformin as a therapeutic target in endometrial cancers. Front. Oncol. 2018, 8, 341. [Google Scholar] [CrossRef]
  58. Hua, L.; Zhang, L.; Zhang, X.; Cui, Z. PI3K/AKT/mTOR pathway promotes progestin resistance in endometrial cancer cells by inhibition of autophagy. OncoTargets Ther. 2017, 10, 2865–2871. [Google Scholar]
  59. Mabuchi, S.; Kuroda, H.; Takahashi, R.; Sasano, T. The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer. Gynecol. Oncol. 2015, 137, 173–179. [Google Scholar] [CrossRef]
  60. Levine, D.A.; Bogomolniy, F.; Yee, C.J.; Lash, A.; Barakat, R.R.; Borgen, P.I.; Boyd, J. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin. Cancer Res. 2005, 11, 2875–2878. [Google Scholar] [CrossRef] [Green Version]
  61. Andorfer, P.; Heuwieser, A.; Heinzel, A.; Lukas, A.; Mayer, B.; Perco, P. Vascular endothelial growth factor A as predictive marker for mTOR inhibition in relapsing high-grade serous ovarian cancer. BMC Syst. Biol. 2016, 10, 33. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011, 474, 609–615. [Google Scholar] [CrossRef]
  63. Stemke-Hale, K.; Gonzalez-Angulo, A.M.; Lluch, A.; Neve, R.M.; Kuo, W.L.; Davies, M.; Carey, M.; Hu, Z.; Guan, Y.; Sahin, A.; et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008, 68, 6084–6091. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Liang, H.; Cheung, L.W.; Li, J.; Ju, Z.; Yu, S.; Stemke-Hale, K.; Dogruluk, T.; Lu, Y.; Liu, X.; Gu, C.; et al. Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer. Genome Res. 2012, 22, 2120–2129. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Netti, G.S.; Lucarelli, G.; Spadaccino, F.; Castellano, G.; Gigante, M.; Divella, C.; Rocchetti, M.T.; Rascio, F.; Mancini, V.; Stallone, G.; et al. PTX3 modulates the immunoflogosis in tumor microenvironment and is a prognostic factor for patients with clear cell renal cell carcinoma. Aging (Albany NY) 2020, 12, 7585–7602. [Google Scholar] [CrossRef] [PubMed]
  66. Lucarelli, G.; Ditonno, P.; Bettocchi, C.; Vavallo, A.; Rutigliano, M.; Galleggiante, V.; Larocca, A.M.; Castellano, G.; Gesualdo, L.; Grandaliano, G.; et al. Diagnostic and prognostic role of preoperative circulating CA 15-3, CA 125, and beta-2 microglobulin in renal cell carcinoma. Dis. Markers 2014, 2014, 689795. [Google Scholar] [CrossRef]
  67. Dawood, M.; Mills, G.B.; Ding, Z. Shrewd AKT regulation to survive. Oncoscience 2014, 1, 113–114. [Google Scholar] [CrossRef] [Green Version]
  68. Fan, D.; Liu, Q.; Wu, F.; Liu, N.; Qu, H.; Yuan, Y.; Li, Y.; Gao, H.; Ge, J.; Xu, Y.; et al. Prognostic significance of PI3K/AKT/mTOR signaling pathway members in clear cell renal cell carcinoma. PeerJ 2020, 8, e9261. [Google Scholar] [CrossRef]
  69. Huang, J.; Wang, X.; Wen, G.; Ren, Y. miRNA-205-5p functions as a tumor suppressor by negatively regulating VEGFA and PI3K/Akt/mTOR signaling in renal carcinoma cells. Oncol. Rep. 2019, 42, 1677–1688. [Google Scholar] [CrossRef]
  70. Hoxhaj, G.; Manning, B.D. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat. Rev. Cancer 2020, 20, 74–88. [Google Scholar] [CrossRef]
  71. Taheri, M.; Shirvani-Farsani, Z.; Ghafouri-Fard, S. Expression profile of microRNAs in bladder cancer and their application as biomarkers. Biomed. Pharmacother. 2020, 131, 110703. [Google Scholar] [CrossRef]
  72. O’Brien, J.; Hayder, H.; Zayed, Y.; Peng, C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Front. Endocrinol. 2018, 9, 402. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Spadaccino, F.; Gigante, M.; Netti, G.S.; Rocchetti, M.T.; Franzin, R.; Gesualdo, L.; Castellano, G.; Stallone, G.; Ranieri, E. The ambivalent role of miRNAs in carcinogenesis: Involvement in renal cell carcinoma and their clinical applications. Pharmaceuticals 2021, 14, 322. [Google Scholar] [CrossRef] [PubMed]
  74. Xu, M.; Mo, Y.Y. The Akt-associated microRNAs. Cell. Mol. Life Sci. 2012, 69, 3601–3612. [Google Scholar] [CrossRef] [Green Version]
  75. Xu, X.; Wu, J.; Li, S.; Hu, Z.; Xu, X.; Zhu, Y.; Liang, Z.; Wang, X.; Lin, Y.; Mao, Y.; et al. Downregulation of microRNA-182-5p contributes to renal cell carcinoma proliferation via activating the AKT/FOXO3a signaling pathway. Mol. Cancer 2014, 13, 109. [Google Scholar] [CrossRef] [Green Version]
  76. Lian, J.H.; Wang, W.H.; Wang, J.Q.; Zhang, Y.H.; Li, Y. MicroRNA-122 promotes proliferation, invasion and migration of renal cell carcinoma cells through the PI3K/Akt signaling pathway. Asian Pac. J. Cancer Prev. 2013, 14, 5017–5021. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Xu, X.W.; Li, S.; Yin, F.; Qin, L.L. Expression of miR-205 in renal cell carcinoma and its association with clinicopathological features and prognosis. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 662–670. [Google Scholar]
  78. Zhang, Z.; Li, Z.; Li, Y.; Zang, A. MicroRNA and signaling pathways in gastric cancer. Cancer Gene Ther. 2014, 21, 305–316. [Google Scholar] [CrossRef] [Green Version]
  79. Matsuoka, T.; Yashiro, M. The role of PI3K/Akt/mTOR signaling in gastric carcinoma. Cancers 2014, 6, 1441–1463. [Google Scholar] [CrossRef] [Green Version]
  80. Kang, Y.H.; Lee, H.S.; Kim, W.H. Promoter methylation and silencing of PTEN in gastric carcinoma. Lab. Investig. 2002, 82, 285–291. [Google Scholar] [CrossRef] [Green Version]
  81. Yang, S.M.; Huang, C.; Li, X.F.; Yu, M.Z.; He, Y.; Li, J. miR-21 confers cisplatin resistance in gastric cancer cells by regulating PTEN. Toxicology 2013, 306, 162–168. [Google Scholar] [CrossRef]
  82. Zhang, H.; Qu, Y.; Jingjing, D.; Deng, T.; Liu, R.; Zhang, L.; Bai, M.; Li, J.; Zhou, L.; Ning, T.; et al. Integrated analysis of the miRNA, gene and pathway regulatory network in gastric cancer. Oncol. Rep. 2016, 35, 1135–1146. [Google Scholar] [CrossRef]
  83. Li, N.A.; Wang, W.; Xu, B.; Gong, H. miR-196b regulates gastric cancer cell proliferation and invasion via PI3K/AKT/mTOR signaling pathway. Oncol. Lett. 2016, 11, 1745–1749. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Tsukamoto, Y.; Nakada, C.; Noguchi, T.; Tanigawa, M.; Nguyen, L.T.; Uchida, T.; Hujiya, N.; Matsuura, K.; Fujioka, T.; Seto, M.; et al. MicroRNA-375 is downregulated in gastric carcinomas and regulates cell survival by targeting PDK1 and 14-3-3zeta. Cancer Res. 2010, 70, 2339–2349. [Google Scholar] [CrossRef] [Green Version]
  85. Peng, Y.; Guo, J.J.; Liu, Y.M.; Wu, X.L. MicroRNA-34 inhibits the growth, invasion, and metastasis of gastric cancer by targeting PDGFR and MET expression. Biosci. Rep. 2014, 34, e00112. [Google Scholar] [CrossRef]
  86. Wang, T.; Hou, J.; Li, Z.; Zheng, Z.; Wei, J.; Song, D.; Hu, T.; Wu, Q.; Yang, J.Y.; Cai, J.C. miR-15a-3p and miR-16-1-3p negatively regulate twist1 to repress gastric cancer cell invasion and metastasis. Int. J. Biol. Sci. 2017, 13, 122–134. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Kang, W.; Tong, J.H.M.; Lung, R.W.M.; Dong, Y.; Zhao, J.; Liang, Q.; Zhang, L.; Pan, Y.; Yang, W.; Pang, J.C.S. Targeting of YAP1 by microRNA-15a and microRNA-16-1 exerts tumor suppressor function in gastric adenocarcinoma. Mol. Cancer 2015, 14, 52. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Wu, L.; Chen, J.; Ding, C.; Wei, S.; Zhu, Y.; Yang, W.; Zhang, X.; Wei, X.; Han, D. MicroRNA-137 contributes to dampened tumorigenesis in human gastric cancer by Targeting AKT2. PLoS ONE 2015, 10, e0130124. [Google Scholar] [CrossRef]
  89. Liang, M.; Shi, B.; Liu, J.; He, L.; Yi, G.; Zhou, L.; Yu, G.; Zhou, X. Downregulation of miR203 induces overexpression of PIK3CA and predicts poor prognosis of gastric cancer patients. Drug Des. Dev. Ther. 2015, 9, 3607–3616. [Google Scholar]
  90. Riquelme, I.; Tapia, O.; Leal, P.; Sandoval, A.; Varga, M.G.; Letelier, P.; Buchegger, K.; Bizama, C.; Espinoza, J.A.; Peek, R.M.; et al. miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in gastric cancer through regulation of the PI3K/AKT/mTOR pathway. Cell. Oncol. (Dordr.) 2016, 39, 23–33. [Google Scholar] [CrossRef] [Green Version]
  91. Deng, Y.; Bai, H.; Hu, H. rs11671784 G/A variation in miR-27a decreases chemo-sensitivity of bladder cancer by decreasing miR-27a and increasing the target RUNX-1 expression. Biochem. Biophys. Res. Commun. 2015, 458, 321–327. [Google Scholar] [CrossRef] [PubMed]
  92. Homami, A.; Ghazi, F. MicroRNAs as biomarkers associated with bladder cancer. Med. J. Islamic Repub. Iran 2016, 30, 475. [Google Scholar]
  93. Magee, P.; Shi, L.; Garofalo, M. Role of microRNAs in chemoresistance. Ann. Transl. Med. 2015, 3, 332. [Google Scholar] [PubMed]
  94. Zhao, X.; Yang, L.; Hu, J. Down-regulation of miR-27a might inhibit proliferation and drug resistance of gastric cancer cells. J. Exp. Clin. Cancer Res. 2011, 30, 55–60. [Google Scholar] [CrossRef] [Green Version]
  95. Li, Z.; Hu, S.; Wang, J.; Cai, J.; Xiao, L.; Yu, L.; Wang, Z. MiR-27a modulates MDR1/P-glycoprotein expression by targeting HIPK2 in human ovarian cancer cells. Gynecol. Oncol. 2010, 119, 125–130. [Google Scholar] [CrossRef]
  96. Feng, D.D.; Zhang, H.; Zhang, P.; Zheng, Y.S.; Zhang, X.J.; Han, B.W.; Luo, X.Q.; Xu, L.; Zhou, H.; Qu, L.H.; et al. Down-regulated miR-331-5p and miR-27a are associated with chemotherapy resistance and relapse in leukaemia. J. Cell. Mol. Med. 2011, 15, 2164–2175. [Google Scholar] [CrossRef] [Green Version]
  97. Chen, Z.; Ma, T.; Huang, C.; Zhang, L.; Lv, X.; Xu, T.; Hu, T.; Li, J. MiR-27a modulates the MDR1/P-glycoprotein expression by inhibiting FZD7/β-catenin pathway in hepatocellular carcinoma cells. Cell. Signal. 2013, 25, 2693–2701. [Google Scholar] [CrossRef]
  98. Zhu, B.; Chen, W.; Fu, Y.; Cui, X.; Jin, L.; Chao, J.; Yun, X.; Gao, P.; Shan, S.; Li, J.; et al. MicroRNA-27a-3p Reverses Adriamycin Resistance by Targeting BTG2 and Activating PI3K/Akt Pathway in Breast Cancer Cells. OncoTargets Ther. 2020, 13, 6873–6884. [Google Scholar] [CrossRef] [PubMed]
  99. Geng, W.; Song, H.; Zhao, Q.; Dong, K.; Pu, Q.; Gao, H.; Lv, Y. miR-520h Stimulates Drug Resistance to Paclitaxel by Targeting the OTUD3-PTEN Axis in Breast Cancer. Biomed. Res. Int. 2020, 9512793. [Google Scholar] [CrossRef]
  100. Cretella, D.; Digiacomo, G.; Giovannetti, E.; Cavazzoni, A. PTEN alterations as a potential mechanism for tumor cell escape from PD-1/PD-L1 inhibition. Cancers 2019, 11, 1318. [Google Scholar] [CrossRef] [Green Version]
  101. Luongo, F.; Colonna, F.; Calapa, F.; Vitale, S.; Fiori, M.E.; De Maria, R. PTEN tumor-suppressor: The dam of stemness in cancer. Cancers 2019, 11, 1076. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Maehama, T.; Taylor, G.S.; Dixon, J.E. PTEN and myotubularin: Novel phosphoinositide phosphatases. Annu. Rev. Biochem. 2001, 70, 247–279. [Google Scholar] [CrossRef]
  103. Sugiyama, M.G.; Fairn, G.D.; Antonescu, C.N. Akt-ing Up Just About Everywhere: Compartment-Specific Akt Activation and Function in Receptor Tyrosine Kinase Signaling. Front. Cell Dev. Biol. 2019, 7, 70. [Google Scholar] [CrossRef] [PubMed]
  104. Leslie, N.R.; Downes, C.P. PTEN function: How normal cells control it and tumour cells lose it. Biochem. J. 2004, 382, 1–11. [Google Scholar] [CrossRef] [Green Version]
  105. Fu, Q.; Huang, Y.; Ge, C.; Li, Z.; Tian, H.; Li, Q.; Li, H.; Li, R.; Tao, X.; Xue, Y.; et al. SHIP1 inhibits cell growth, migration, and invasion in non-small cell lung cancer through the PI3K/AKT pathway. Oncol. Rep. 2019, 41, 2337–2350. [Google Scholar] [CrossRef]
  106. Eramo, M.J.; Mitchell, C.A. Regulation of PtdIns (3,4,5) P3/Akt signalling by inositol polyphosphate 5-phosphatases. Biochem. Soc. Trans. 2016, 44, 240–252. [Google Scholar] [CrossRef] [Green Version]
  107. Duarte, A.; Silveira, G.G.; Soave, D.F.; Costa, J.P.O.; Silva, A.R. The role of the LY294002—A non-selective inhibitor of phosphatidylinositol 3-kinase (PI3K) pathway—in cell survival and proliferation in cell line SCC-25. Asian Pac. J. Cancer Prev. 2019, 20, 3377–3383. [Google Scholar] [CrossRef] [PubMed]
  108. Bavelloni, A.; Focaccia, E.; Piazzi, M.; Orsini, A.; Ramazzotti, G.; Cocco, L.; Blalock, W.; Faenza, I. Therapeutic potential of nvp-bkm120 in human osteosarcomas cells. J. Cell. Physiol. 2019, 234, 10907–10917. [Google Scholar] [CrossRef]
  109. Hainsworth, J.D.; Becker, K.P.; Mekhail, T.; Chowdhary, S.A.; Eakle, J.F.; Wright, D.; Langdon, R.M.; Yost, K.J.; Padula, G.D.A.; West-Osterfield, K.; et al. Phase I/II study of bevacizumab with BKM120, an oral PI3K inhibitor, in patients with refractory solid tumors (phase I) and relapsed/refractory glioblastoma (phase II). J. Neurooncol. 2019, 144, 303–311. [Google Scholar] [CrossRef]
  110. Weinberg, M.A. RES-529: A PI3K/AKT/mTOR pathway inhibitor that dissociates the mTORC1 and mTORC2 complexes. Anticancer Drugs 2016, 27, 475–487. [Google Scholar] [CrossRef] [PubMed]
  111. Kaley, T.J.; Panageas, K.S.; Mellinghoff, I.K.; Nolan, C.; Gavrilovic, I.T.; De Angelis, L.M.; Abrey, L.E.; Holland, E.C.; Lassman, A.B. Phase II trial of an AKT inhibitor (perifosine) for recurrent glioblastoma. J. Neurooncol. 2019, 144, 403–407. [Google Scholar] [CrossRef] [PubMed]
  112. Peng, K.; Fan, X.; Li, Q.; Wang, Y.; Chen, X.; Xiao, P.; Passerini, A.G.; Simon, S.I.; Sun, C. IRF-1 mediates the suppressive effects of mTOR inhibition on arterial endothelium. J. Mol. Cell. Cardiol. 2020, 140, 30–41. [Google Scholar] [CrossRef]
  113. Mendez-Gomez, M.; Castro-Mercado, E.; Pena-Uribe, C.A.; Reyes-de la Cruz, H.; Lopez-Bucio, J.; Garcia-Pineda, E. TARGET OF RAPAMYCIN signaling plays a role in Arabidopsis growth promotion by Azospirillum brasilense Sp245. Plant Sci. 2020, 293, 110416. [Google Scholar] [CrossRef] [PubMed]
  114. Formisano, L.; Napolitano, F.; Rosa, R.; D’Amato, V.; Servetto, A.; Marciano, R.; De Placido, P.; Bianco, C.; Bianco, R. Mechanisms of resistance to mTOR inhibitors. Crit. Rev. Oncol. Hematol. 2020, 147, 102886. [Google Scholar] [CrossRef]
  115. Brakemeier, S.; Arns, W.; Lehner, F.; Witzke, O.; Vonend, O.; Sommerer, C.; Muhlfeld, A.; Rath, T.; Schuhmann, R.; Zukunft, B.; et al. Everolimus in de novo kidney transplant recipients participating in the Eurotransplant senior program: Results of a prospective randomized multicenter study (SENATOR). PLoS ONE 2019, 14, e0222730. [Google Scholar] [CrossRef]
  116. Schotz, U.; Balzer, V.; Brandt, F.W.; Ziemann, F.; Subtil, F.S.B.; Rieckmann, T.; Kocher, S.; Engenhart-Cabillic, R.; Dikomey, E.; Wittig, A.; et al. Dual PI3K/mTOR inhibitor NVP-BEZ235 enhances radiosensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines due to suppressed double-strand break (DSB) repair by non-homologous end joining. Cancers 2020, 12, 467. [Google Scholar] [CrossRef] [Green Version]
  117. Soltani, A.; Torki, S.; Ghahfarokhi, M.S.; Jami, M.S. & Ghatrehsamani; M. Targeting the phosphoinositide 3-kinase/AKT pathways by small molecules and natural compounds as a therapeutic approach for breast cancer cells. Mol. Biol. Rep. 2019, 46, 4809–4816. [Google Scholar]
  118. Chen, Y.; Wang, T.; Du, J.; Li, Y.; Wang, X.; Zhou, Y.; Yu, X.; Fan, W.; Zhu, Q.; Tong, X.; et al. The Critical Role of PTEN/PI3K/AKT Signaling Pathway in Shikonin-Induced Apoptosis and Proliferation Inhibition of Chronic Myeloid Leukemia. Cell. Physiol. Biochem. 2018, 47, 981–993. [Google Scholar] [CrossRef]
  119. Wu, D.M.; Zhang, T.; Liu, Y.B.; Deng, S.H.; Han, R.; Liu, T.; Li, J.; Xu, Y. The PAX6-ZEB2 axis promotes metastasis and cisplatin resistance in non-small cell lung cancer through PI3K/AKT signaling. Cell Death Dis. 2019, 10, 349. [Google Scholar] [CrossRef] [PubMed]
  120. Ediriweera, M.K.; Tennekoon, K.H.; Samarakoon, S.R. Role of the PI3K/AKT/mTOR signaling pathway in ovarian cancer: Biological and therapeutic significance. Semin. Cancer Biol. 2019, 59, 147–160. [Google Scholar] [CrossRef]
  121. Rahmani, F.; Ziaeemehr, A.; Shahidsales, S.; Gharib, M.; Khazaei, M.; Ferns, G.A.; Ryzhikov, M.; Avan, A.; Hassanian, S.M. Role of regulatory miRNAs of the PI3K/AKT/mTOR signaling in the pathogenesis of hepatocellular carcinoma. J. Cell. Physiol. 2020, 235, 4146–4152. [Google Scholar] [CrossRef] [PubMed]
  122. Rittler, D.; Baranyi, M.; Molnár, E.; Garay, T.; Jalsovszky, I.; Varga, I.K.; Hegedűs, L.; Aigner, C.; Tóvári, J.; Tímár, J.; et al. The Antitumor Effect of Lipophilic Bisphosp honate BPH1222 in Melanoma Models: The Role of the PI3K/Akt Pathway and the Small G Protein Rheb. Int. J. Mol. Sci. 2019, 20, 4917. [Google Scholar] [CrossRef] [Green Version]
  123. Rocha Gda, G.; Oliveira, R.R.; Kaplan, M.A.; Gattass, C.R. 3β-Acetyl tormentic acid reverts MRP1/ABCC1 mediated cancer resistance through modulation of intracellular levels of GSH and inhibition of GST activity. Eur. J. Pharmacol. 2014, 741, 140–149. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Choi, E.; Kim, E.; Kim, J.H.; Yoon, K.; Kim, S.; Lee, J.; Cho, J.Y. AKT1-targeted proapoptotic activity of compound K in human breast cancer cells. J. Ginseng Res. 2019, 43, 692–698. [Google Scholar] [CrossRef]
  125. Adams, J.M.; Cory, S. The BCL-2 arbiters of apoptosis and their growing role as cancer targets. Cell Death Differ. 2018, 25, 27–36. [Google Scholar] [CrossRef] [Green Version]
  126. Reed, J.C. Bcl-2 on the brink of breakthroughs in cancer treatment. Cell Death Differ. 2018, 25, 3–6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. García-Aranda, M.; Pérez-Ruiz, E.; Redondo, M. Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy. Int. J. Mol. Sci. 2018, 19, 3950. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Huang, Q.; Li, S.; Cheng, P.; Deng, M.; He, X.; Wang, Z.; Yang, C.H.; Zhao, X.Y.; Huang, J. High expression of anti-apoptotic protein Bcl-2 is a good prognostic factor in colorectal cancer: Result of a meta-analysis. World J. Gastroenterol. 2017, 23, 5018. [Google Scholar] [CrossRef] [PubMed]
  129. Itoi, T.; Yamana, K.; Bilim, V.; Takahashi, K.; Tomita, F. Impact of frequent Bcl-2 expression on better prognosis in renal cell carcinoma patients. Br. J. Cancer. 2004, 90, 200–205. [Google Scholar] [CrossRef] [PubMed]
  130. Shibata, Y.; Hidaka, S.; Tagawa, Y.; Nagayasu, T. Bcl-2 protein expression correlates with better prognosis in patients with advanced non-small cell lung cancer. Anticancer Res. 2004, 24, 1925–1928. [Google Scholar]
  131. Huang, X.; Wu, Z.; Mei, Y.; Wu, M. XIAP inhibits autophagy via XIAP-Mdm2-p53 signalling. EMBO J. 2013, 32, 2204–2216. [Google Scholar] [CrossRef] [Green Version]
  132. Hussain, A.R.; Bu, R.; Ahmed, M.; Jehan, Z.; Beg, S.; Al-Sobhi, S.; Al-Dayel, F.; Siraj, A.K.; Uddin, S.; Al-Kuraya, K.S. Role of X-linked inhibitor of apoptosis as a prognostic marker and therapeutic target in papillary thyroid carcinoma. J. Clin. Endocrinol. Metab. 2015, 100, E974–E985. [Google Scholar] [CrossRef] [Green Version]
  133. Xiang, G.; Wen, X.; Wang, H.; Chen, K.; Liu, H. Expression of X-linked inhibitor of apoptosis protein in human colorectal cancer and its correlation with prognosis. J. Surg. Oncol. 2009, 100, 708–712. [Google Scholar]
  134. Augello, C.; Caruso, L.; Maggioni, M.; Donadon, M.; Montorsi, M.; Santambrogio, R.; Torzilli, G.; Vaira, V.; Pellegrini, C.; Roncalli, M.; et al. Inhibitors of apoptosis proteins (IAPs) expression and their prognostic significance in hepatocellular carcinoma. BMC Cancer 2009, 9, 125. [Google Scholar] [CrossRef]
  135. Esposito, I.; Kleeff, J.; Abiatari, I.; Shi, X.; Giese, N.; Bergmann, F.; Roth, W.; Friess, H.; Schirmacher, P. Overexpression of cellular inhibitor of apoptosis protein 2 is an early event in the progression of pancreatic cancer. J. Clin. Pathol. 2007, 60, 885–895. [Google Scholar] [CrossRef] [Green Version]
  136. Che, X.; Yang, D.; Zong, H.; Wang, J.; Li, X.; Chen, F.; Chen, X.; Song, X. Nuclear cIAP1 overexpression is a tumor stage- and grade-independent predictor of poor prognosis in human bladder cancer patients. Urol. Oncol. 2012, 30, 450–456. [Google Scholar] [CrossRef] [PubMed]
  137. Hussain, A.R.; Siraj, A.K.; Ahmed, M.; Bu, R.; Pratheeshkumar, P.; Alrashed, A.M.; Qadri, Z.; Ajarim, D.; Al-Dayel, F.; Beg, S.; et al. XIAP over-expression is an independent poor prognostic marker in Middle Eastern breast cancer and can be targeted to induce efficient apoptosis. BMC Cancer 2017, 17, 640. [Google Scholar] [CrossRef] [PubMed]
  138. Mahadevan, D.; Chalasani, P.; Rensvold, D.; Kurtin, S.; Pretzinger, C.; Jolivet, J.; Ramanathan, R.K.; Von Hoff, D.D.; Weiss, G.J. Phase I trial of AEG35156 an antisense oligonucleotide to XIAP plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma. Am. J. Clin. Oncol. 2013, 36, 239–243. [Google Scholar] [CrossRef] [PubMed]
  139. Mannhold, R.; Fulda, S.; Carosati, E. IAP antagonists: Promising candidates for cancer therapy. Drug Discov. Today 2010, 15, 210–219. [Google Scholar] [CrossRef] [PubMed]
  140. Chen, P.; Zhang, J.; Sha, B.; Ma, Y.; Hu, T.; Ma, Y.; Sun, H.; Shi, J.; Dong, Z.; Li, P. Luteolin inhibits cell proliferation and induces cell apoptosis via down-regulation of mitochondrial membrane potential in esophageal carcinoma cells EC1 and KYSE450. Oncotarget 2017, 8, 27471–27480. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  141. Brown, K.K.; Toker, A. The phosphoinositide 3-kinase pathway and therapy resistance in cancer. F1000prime Rep. 2015, 7, 13. [Google Scholar] [CrossRef]
  142. Hu, Y.; Guo, R.; Wei, J.; Zhou, Y.; Ji, W.; Liu, J.; Zhi, X.; Zhang, J. Effects of PI3K inhibitor NVP-BKM120 on overcoming drug resistance and eliminating cancer stem cells in human breast cancer cells. Cell Death Dis. 2015, 6, e2020. [Google Scholar] [CrossRef] [PubMed]
  143. Eberle, J. Countering TRAIL Resistance in Melanoma. Cancers 2019, 11, 656. [Google Scholar] [CrossRef] [Green Version]
  144. Kumar, S.; Kushwaha, P.P.; Gupta, S. Emerging targets in cancer drug resistance. Cancer Drug Resist. 2019, 2, 161–177. [Google Scholar] [CrossRef] [Green Version]
  145. Knuefermann, C.; Lu, Y.; Liu, B.; Jin, W.; Liang, K.; Wu, L.; Schmidt, M.; Mills, G.B.; Mendelsohn, J.; Fan, Z. HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene 2003, 22, 3205–3212. [Google Scholar] [CrossRef] [Green Version]
  146. Luo, H.; Cong, S.; Dong, J.; Jin, L.; Jiang, D.; Wang, X.; Chen, Q.; Li, F. Paired-related homeobox 1 overexpression promotes multidrug resistance via PTEN/PI3K/AKT signaling in MCF-7 breast cancer cells. Mol. Med. Rep. 2020, 4, 3183–3190. [Google Scholar] [CrossRef] [PubMed]
  147. Si, W.; Shen, J.; Zheng, H.; Fan, W. The role and mechanisms of action of microRNAs in cancer drug resistance. Clin. Epigenet. 2019, 11, 25. [Google Scholar] [CrossRef] [PubMed]
  148. Miled, N.; Yan, Y.; Hon, W.C.; Perisic, O.; Zvelebil, M.; Inbar, Y.; Schneidman-Duhovny, D.; Wolfson, H.J.; Backer, J.M.; Williams, R.L. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 2007, 317, 239–242. [Google Scholar] [CrossRef] [Green Version]
  149. Meng, Y.; Lin, Z.M.; Ge, N.; Zhang, D.L.; Huang, J.; Kong, F. Ursolic Acid Induces Apoptosis of Prostate Cancer Cells via the PI3K/Akt/mTOR Pathway. Am. J. Chin. Med. 2015, 43, 1471–1486. [Google Scholar] [CrossRef]
  150. Dong, C.; Chen, Y.; Ma, J.; Yang, R.; Li, H.; Liu, R.; You, D.; Luo, C.; Li, H.; Yang, S.; et al. Econazole nitrate reversed the resistance of breast cancer cells to Adriamycin through inhibiting the PI3K/AKT signaling pathway. Am. J. Cancer Res. 2020, 10, 263–274. [Google Scholar]
  151. Annageldiyev, C.; Tan, S.F.; Thakur, S.; Dhanyamraju, P.K.; Ramisetti, S.R.; Bhadauria, P.; Schick, J.; Zeng, Z.; Sharma, V.; Dunton, W.; et al. The PI3K/AKT Pathway Inhibitor ISC-4 Induces Apoptosis and Inhibits Growth of Leukemia in Preclinical Models of Acute Myeloid Leukemia. Front. Oncol. 2020, 10, 393. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Abbas, R.; Larisch, S. Targeting XIAP for Promoting Cancer Cell Death—The Story of ARTS and SMAC. Cells 2020, 9, 663. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Zhang, Y.; Wang, Z.; Gemeinhart, R.A. Progress in microRNA delivery. J. Control. Release 2013, 172, 962–974. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Cancers 13 03949 g001 550
Figure 1. Involvement of PI3K/Akt/mTOR signalling pathways in the development of cancers. As illustrated, the auto-phosphorylation of PI3K leads to the activation of Akt, through PIP2 to PIP3 conversion. PI3K/Akt and mTORC1 contribute to tumour growth and the energy storage of cancer cells. The upregulation of Akt Promotes the phosphorylation of target genes and proteins which promote the inhibition of apoptosis and autophagy. Deregulated miRNAs also contribute to cancer cell proliferation.
Figure 1. Involvement of PI3K/Akt/mTOR signalling pathways in the development of cancers. As illustrated, the auto-phosphorylation of PI3K leads to the activation of Akt, through PIP2 to PIP3 conversion. PI3K/Akt and mTORC1 contribute to tumour growth and the energy storage of cancer cells. The upregulation of Akt Promotes the phosphorylation of target genes and proteins which promote the inhibition of apoptosis and autophagy. Deregulated miRNAs also contribute to cancer cell proliferation.
Cancers 13 03949 g001
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Rascio, F.; Spadaccino, F.; Rocchetti, M.T.; Castellano, G.; Stallone, G.; Netti, G.S.; Ranieri, E. The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review. Cancers 2021, 13, 3949. https://doi.org/10.3390/cancers13163949

AMA Style

Rascio F, Spadaccino F, Rocchetti MT, Castellano G, Stallone G, Netti GS, Ranieri E. The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review. Cancers. 2021; 13(16):3949. https://doi.org/10.3390/cancers13163949

Chicago/Turabian Style

Rascio, Federica, Federica Spadaccino, Maria Teresa Rocchetti, Giuseppe Castellano, Giovanni Stallone, Giuseppe Stefano Netti, and Elena Ranieri. 2021. "The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review" Cancers 13, no. 16: 3949. https://doi.org/10.3390/cancers13163949

APA Style

Rascio, F., Spadaccino, F., Rocchetti, M. T., Castellano, G., Stallone, G., Netti, G. S., & Ranieri, E. (2021). The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review. Cancers, 13(16), 3949. https://doi.org/10.3390/cancers13163949

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop