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PI3K/PDK1/Akt Pathways in Cancer
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PI3K/PDK1/Akt Pathways in Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 January 2017) | Viewed by 77964

Special Issue Editor

Prof. Dr. Marco Falasca

E-Mail Website
Guest Editor
Department of Medicine and Surgery, University of Parma, Via Volturno, 39, 43125 Parma, Italy
Interests: lipid metabolism; gastrointestinal diseases; pancreatic cancer; extracellular vesicles; tumour-stroma crosstalk; cannabinoid signalling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Phosphoinositide 3-kinases (PI3Ks) enzymes are important signalling molecules involved in a variety of different cellular functions. They use phosphoinositides as substrates and they exert their function through phosphorylation of the D3 position within the inositol ring, generating PtdIns3P, PtdIns(3,4)P2 and PtdIns(3,4,5)P3. The PI3K family contains eight mammalian isoforms grouped into three classes in accordance with substrate specificity and structure. Interestingly, there is a variety of genetic abnormalities observed in the PI3K pathway in cancer, such as activating and deactivating mutations and post-transcriptional epigenetic irregularities. It is a common phenomenon in solid tumours to witness aberrant PI3Kα activity, directly or indirectly resulting from mutations of the respective gene; therefore PI3Kα inhibition is an emerging approach for treating these types of tumours and indeed there are a number of relevant ongoing trials. Nevertheless, emerging evidence supports the role of other PI3K isoforms in cancer as well as the complexity and specificity of activation of PI3K downstream effectors. Indeed, novel signaling pathways and cell functions are continuously identified as regulated by PI3K isoforms in cancer. The combined data indicate that the biological functions of PI3K isoforms are far more complex than presently known and that the overall responses to PI3K-inhibiting drugs are likely to be context-dependent. This Special Issue will cover the recent progress in all areas related to PI3K signaling and cancer.

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Keywords

  • Phosphoinositides 3-Kinases
  • cell signalling
  • phosphoinositides
  • cancer
  • drug resistance
  • 3-phosphoinositide dependent protein kinase-1
  • Protein kinase B/Akt

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Published Papers (9 papers)

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Research

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1836 KiB  
Article
Timp1 Promotes Cell Survival by Activating the PDK1 Signaling Pathway in Melanoma
by Mariana Toricelli, Fabiana H. M. Melo, Aline Hunger, Daniela Zanatta, Bryan E. Strauss and Miriam G. Jasiulionis
Cancers 2017, 9(4), 37; https://doi.org/10.3390/cancers9040037 - 21 Apr 2017
Cited by 23 | Viewed by 6876
Abstract
High TIMP1 expression is associated with poor prognosis in melanoma, where it can bind to CD63 and β1 integrin, inducing PI3-kinase pathway and cell survival. Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), generated under phosphatidylinositol-3-kinase (PI3K) activation, enables the recruitment and activation of protein kinase B (PKB/AKT) [...] Read more.
High TIMP1 expression is associated with poor prognosis in melanoma, where it can bind to CD63 and β1 integrin, inducing PI3-kinase pathway and cell survival. Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), generated under phosphatidylinositol-3-kinase (PI3K) activation, enables the recruitment and activation of protein kinase B (PKB/AKT) and phosphoinositide-dependent kinase 1 (PDK1) at the membrane, resulting in the phosphorylation of a host of other proteins. Using a melanoma progression model, we evaluated the impact of Timp1 and AKT silencing, as well as PI3K, PDK1, and protein kinase C (PKC) inhibitors on aggressiveness characteristics. Timp1 downregulation resulted in decreased anoikis resistance, clonogenicity, dacarbazine resistance, and in vivo tumor growth and lung colonization. In metastatic cells, pAKTThr308 is highly expressed, contributing to anoikis resistance. We showed that PDK1Ser241 and PKCβIISer660 are activated by Timp1 in different stages of melanoma progression, contributing to colony formation and anoikis resistance. Moreover, simultaneous inhibition of Timp1 and AKT in metastatic cells resulted in more effective anoikis inhibition. Our findings demonstrate that Timp1 promotes cell survival with the participation of PDK1 and PKC in melanoma. In addition, Timp1 and AKT act synergistically to confer anoikis resistance in advanced tumor stages. This study brings new insights about the mechanisms by which Timp1 promotes cell survival in melanoma, and points to novel perspectives for therapeutic approaches. Full article
(This article belongs to the Special Issue PI3K/PDK1/Akt Pathways in Cancer)
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Review

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2019 KiB  
Review
Targeting PDK1 for Chemosensitization of Cancer Cells
by Aikaterini Emmanouilidi and Marco Falasca
Cancers 2017, 9(10), 140; https://doi.org/10.3390/cancers9100140 - 24 Oct 2017
Cited by 48 | Viewed by 12549
Abstract
Despite the rapid development in the field of oncology, cancer remains the second cause of mortality worldwide, with the number of new cases expected to more than double in the coming years. Chemotherapy is widely used to decelerate or stop tumour development in [...] Read more.
Despite the rapid development in the field of oncology, cancer remains the second cause of mortality worldwide, with the number of new cases expected to more than double in the coming years. Chemotherapy is widely used to decelerate or stop tumour development in combination with surgery or radiation therapy when appropriate, and in many cases this improves the symptomatology of the disease. Unfortunately though, chemotherapy is not applicable to all patients and even when it is, there are many cases where a successful initial treatment period is followed by chemotherapeutic drug resistance. This is caused by a number of reasons, ranging from the genetic background of the patient (innate resistance) to the formation of tumour-initiating cells (acquired resistance). In this review, we discuss the potential role of PDK1 in the development of chemoresistance in different types of malignancy, and the design and application of potent inhibitors which can promote chemosensitization. Full article
(This article belongs to the Special Issue PI3K/PDK1/Akt Pathways in Cancer)
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1081 KiB  
Review
Phosphoinositide 3-Kinase-Dependent Signalling Pathways in Cutaneous Squamous Cell Carcinomas
by Joanna M. Janus, Ryan F. L. O’Shaughnessy, Catherine A. Harwood and Tania Maffucci
Cancers 2017, 9(7), 86; https://doi.org/10.3390/cancers9070086 - 11 Jul 2017
Cited by 34 | Viewed by 6774
Abstract
Cutaneous squamous cell carcinoma (cSCC) derives from keratinocytes in the epidermis and accounts for 15–20% of all cutaneous malignancies. Although it is usually curable by surgery, 5% of these tumours metastasise leading to poor prognosis mostly because of a lack of therapies and [...] Read more.
Cutaneous squamous cell carcinoma (cSCC) derives from keratinocytes in the epidermis and accounts for 15–20% of all cutaneous malignancies. Although it is usually curable by surgery, 5% of these tumours metastasise leading to poor prognosis mostly because of a lack of therapies and validated biomarkers. As the incidence rate is rising worldwide it has become increasingly important to better understand the mechanisms involved in cSCC development and progression in order to develop therapeutic strategies. Here we discuss some of the evidence indicating that activation of phosphoinositide 3-kinases (PI3Ks)-dependent signalling pathways (in particular the PI3Ks targets Akt and mTOR) has a key role in cSCC. We further discuss available data suggesting that inhibition of these pathways can be beneficial to counteract the disease. With the growing number of different inhibitors currently available, it would be important to further investigate the specific contribution of distinct components of the PI3Ks/Akt/mTOR pathways in order to identify the most promising molecular targets and the best strategy to inhibit cSCC. Full article
(This article belongs to the Special Issue PI3K/PDK1/Akt Pathways in Cancer)
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1376 KiB  
Review
Promotion of Tumor Invasion by Tumor-Associated Macrophages: The Role of CSF-1-Activated Phosphatidylinositol 3 Kinase and Src Family Kinase Motility Signaling
by Amy R. Dwyer, Eloise L. Greenland and Fiona J. Pixley
Cancers 2017, 9(6), 68; https://doi.org/10.3390/cancers9060068 - 18 Jun 2017
Cited by 58 | Viewed by 10268
Abstract
Macrophages interact with cells in every organ to facilitate tissue development, function and repair. However, the close interaction between macrophages and parenchymal cells can be subverted in disease, particularly cancer. Motility is an essential capacity for macrophages to be able to carry out [...] Read more.
Macrophages interact with cells in every organ to facilitate tissue development, function and repair. However, the close interaction between macrophages and parenchymal cells can be subverted in disease, particularly cancer. Motility is an essential capacity for macrophages to be able to carry out their various roles. In cancers, the macrophage’s interstitial migratory ability is frequently co-opted by tumor cells to enable escape from the primary tumor and metastatic spread. Macrophage accumulation within and movement through a tumor is often stimulated by tumor cell production of the mononuclear phagocytic growth factor, colony-stimulating factor-1 (CSF-1). CSF-1 also regulates macrophage survival, proliferation and differentiation, and its many effects are transduced by its receptor, the CSF-1R, via phosphotyrosine motif-activated signals. Mutational analysis of CSF-1R signaling indicates that the major mediators of CSF-1-induced motility are phosphatidyl-inositol-3 kinase (PI3K) and one or more Src family kinase (SFK), which activate signals to adhesion, actin polymerization, polarization and, ultimately, migration and invasion in macrophages. The macrophage transcriptome, including that of the motility machinery, is very complex and highly responsive to the environment, with selective expression of proteins and splice variants rarely found in other cell types. Thus, their unique motility machinery can be specifically targeted to block macrophage migration, and thereby, inhibit tumor invasion and metastasis. Full article
(This article belongs to the Special Issue PI3K/PDK1/Akt Pathways in Cancer)
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565 KiB  
Review
Towards Targeting PI3K-Dependent Regulation of Gene Expression in Brain Cancer
by Theo Mantamadiotis
Cancers 2017, 9(6), 60; https://doi.org/10.3390/cancers9060060 - 30 May 2017
Cited by 25 | Viewed by 5589
Abstract
The PI3K pathway is one of the most highly perturbed cell signaling pathways in human cancer, including the most common malignant brain tumors, gliomas, where either activating mutations of positive pathway effectors or loss/inactivation of pathway inhibitors occurs. Knowledge of the precise transcription [...] Read more.
The PI3K pathway is one of the most highly perturbed cell signaling pathways in human cancer, including the most common malignant brain tumors, gliomas, where either activating mutations of positive pathway effectors or loss/inactivation of pathway inhibitors occurs. Knowledge of the precise transcription factors modulated by PI3K in tumor cells remains elusive but there are numerous PI3K-responsive signaling factors, including kinases, which can activate many transcription factors. In the context of cancer, these transcription factors participate in the regulation of target genes expression networks to support cancer cell characteristics such as survival, proliferation, migration and differentiation. This review focuses on the role of PI3K signaling-regulated transcription in brain cancer cells from a series of recent investigations. A deeper understanding of this regulation is beginning to provide the hope of developing more sophisticated anti-cancer targeting approaches, where both upstream and downstream components of the PI3K pathway may be targeted by existing and novel drugs. Full article
(This article belongs to the Special Issue PI3K/PDK1/Akt Pathways in Cancer)
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203 KiB  
Review
PI3K Signaling in Tissue Hyper-Proliferation: From Overgrowth Syndromes to Kidney Cysts
by Maria Chiara De Santis, Valentina Sala, Miriam Martini, Giovanni Battista Ferrero and Emilio Hirsch
Cancers 2017, 9(4), 30; https://doi.org/10.3390/cancers9040030 - 29 Mar 2017
Cited by 36 | Viewed by 5819
Abstract
The members of the PhosphoInositide-3 Kinase (PI3K) protein family are well-known regulators of proliferative signals. By the generation of lipid second messengers, they mediate the activation of AKT/PKB (AKT) and mammalian Target Of Rapamycin (mTOR) pathways. Although mutations in the PI3K/AKT/mTOR pathway are [...] Read more.
The members of the PhosphoInositide-3 Kinase (PI3K) protein family are well-known regulators of proliferative signals. By the generation of lipid second messengers, they mediate the activation of AKT/PKB (AKT) and mammalian Target Of Rapamycin (mTOR) pathways. Although mutations in the PI3K/AKT/mTOR pathway are highly characterized in cancer, recent evidence indicates that alterations in the proliferative signals are major drivers of other diseases such as overgrowth disorders and polycystic kidney disease. In this review, we briefly summarize the role of the PI3K/AKT/mTOR pathway in cell proliferation by comparing the effect of alterations in PI3K enzymes in different tissues. In particular, we discuss the most recent findings on how the same pathway may lead to different biological effects, due to the convergence and cooperation of different signaling cascades. Full article
(This article belongs to the Special Issue PI3K/PDK1/Akt Pathways in Cancer)
1661 KiB  
Review
The Role of PI3K Isoforms in Regulating Bone Marrow Microenvironment Signaling Focusing on Acute Myeloid Leukemia and Multiple Myeloma
by Rachel E. Piddock, Kristian M. Bowles and Stuart A. Rushworth
Cancers 2017, 9(4), 29; https://doi.org/10.3390/cancers9040029 - 28 Mar 2017
Cited by 30 | Viewed by 9002
Abstract
Despite the development of novel treatments in the past 15 years, many blood cancers still remain ultimately fatal and difficult to treat, particularly acute myeloid leukaemia (AML) and multiple myeloma (MM). While significant progress has been made characterising small-scale genetic mutations and larger-scale [...] Read more.
Despite the development of novel treatments in the past 15 years, many blood cancers still remain ultimately fatal and difficult to treat, particularly acute myeloid leukaemia (AML) and multiple myeloma (MM). While significant progress has been made characterising small-scale genetic mutations and larger-scale chromosomal translocations that contribute to the development of various blood cancers, less is understood about the complex microenvironment of the bone marrow (BM), which is known to be a key player in the pathogenesis of chronic lymphocytic leukaemia (CLL), AML and MM. This niche acts as a sanctuary for the cancerous cells, protecting them from chemotherapeutics and encouraging clonal cell survival. It does this by upregulating a plethora of signalling cascades within the malignant cell, with the phosphatidylinositol-3-kinase (PI3K) pathway taking a critical role. This review will focus on how the PI3K pathway influences disease progression and the individualised role of the PI3K subunits. We will also summarise the current clinical trials for PI3K inhibitors and how these trials impact the treatment of blood cancers. Full article
(This article belongs to the Special Issue PI3K/PDK1/Akt Pathways in Cancer)
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1805 KiB  
Review
Serine/Threonine Kinase 3-Phosphoinositide-Dependent Protein Kinase-1 (PDK1) as a Key Regulator of Cell Migration and Cancer Dissemination
by Laura Di Blasio, Paolo A. Gagliardi, Alberto Puliafito and Luca Primo
Cancers 2017, 9(3), 25; https://doi.org/10.3390/cancers9030025 - 11 Mar 2017
Cited by 54 | Viewed by 11237
Abstract
Dissecting the cellular signaling that governs the motility of eukaryotic cells is one of the fundamental tasks of modern cell biology, not only because of the large number of physiological processes in which cell migration is crucial, but even more so because of [...] Read more.
Dissecting the cellular signaling that governs the motility of eukaryotic cells is one of the fundamental tasks of modern cell biology, not only because of the large number of physiological processes in which cell migration is crucial, but even more so because of the pathological ones, in particular tumor invasion and metastasis. Cell migration requires the coordination of at least four major processes: polarization of intracellular signaling, regulation of the actin cytoskeleton and membrane extension, focal adhesion and integrin signaling and contractile forces generation and rear retraction. Among the molecular components involved in the regulation of locomotion, the phosphatidylinositol-3-kinase (PI3K) pathway has been shown to exert fundamental role. A pivotal node of such pathway is represented by the serine/threonine kinase 3-phosphoinositide-dependent protein kinase-1 (PDPK1 or PDK1). PDK1, and the majority of its substrates, belong to the AGC family of kinases (related to cAMP-dependent protein kinase 1, cyclic Guanosine monophosphate-dependent protein kinase and protein kinase C), and control a plethora of cellular processes, downstream either to PI3K or to other pathways, such as RAS GTPase-MAPK (mitogen-activated protein kinase). Interestingly, PDK1 has been demonstrated to be crucial for the regulation of each step of cell migration, by activating several proteins such as protein kinase B/Akt (PKB/Akt), myotonic dystrophy-related CDC42-binding kinases alpha (MRCKα), Rho associated coiled-coil containing protein kinase 1 (ROCK1), phospholipase C gamma 1 (PLCγ1) and β3 integrin. Moreover, PDK1 regulates cancer cell invasion as well, thus representing a possible target to prevent cancer metastasis in human patients. The aim of this review is to summarize the various mechanisms by which PDK1 controls the cell migration process, from cell polarization to actin cytoskeleton and focal adhesion regulation, and finally, to discuss the evidence supporting a role for PDK1 in cancer cell invasion and dissemination. Full article
(This article belongs to the Special Issue PI3K/PDK1/Akt Pathways in Cancer)
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785 KiB  
Review
Class (I) Phosphoinositide 3-Kinases in the Tumor Microenvironment
by David Gyori, Tamara Chessa, Phillip T. Hawkins and Len R. Stephens
Cancers 2017, 9(3), 24; https://doi.org/10.3390/cancers9030024 - 4 Mar 2017
Cited by 32 | Viewed by 8271
Abstract
Phosphoinositide 3-kinases (PI3Ks) are a diverse family of enzymes which regulate various critical biological processes, such as cell proliferation and survival. Class (I) PI3Ks (PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ) mediate the phosphorylation of the inositol ring at position D3 leading to the generation [...] Read more.
Phosphoinositide 3-kinases (PI3Ks) are a diverse family of enzymes which regulate various critical biological processes, such as cell proliferation and survival. Class (I) PI3Ks (PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ) mediate the phosphorylation of the inositol ring at position D3 leading to the generation of PtdIns(3,4,5)P3. PtdIns(3,4,5)P3 can be dephosphorylated by several phosphatases, of which the best known is the 3-phosphatase PTEN (phosphatase and tensin homolog). The Class (I) PI3K pathway is frequently disrupted in human cancers where mutations are associated with increased PI3K-activity or loss of PTEN functionality within the tumor cells. However, the role of PI3Ks in the tumor stroma is less well understood. Recent evidence suggests that the white blood cell-selective PI3Kγ and PI3Kδ isoforms have an important role in regulating the immune-suppressive, tumor-associated myeloid cell and regulatory T cell subsets, respectively, and as a consequence are also critical for solid tumor growth. Moreover, PI3Kα is implicated in the direct regulation of tumor angiogenesis, and dysregulation of the PI3K pathway in stromal fibroblasts can also contribute to cancer progression. Therefore, pharmacological inhibition of the Class (I) PI3K family in the tumor microenvironment can be a highly attractive anti-cancer strategy and isoform-selective PI3K inhibitors may act as potent cancer immunotherapeutic and anti-angiogenic agents. Full article
(This article belongs to the Special Issue PI3K/PDK1/Akt Pathways in Cancer)
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