International Journal of Molecular Sciences

Editorial

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3 pages, 152 KiB

Open AccessEditorial

mTOR in Human Diseases

by Olivier Dormond

Int. J. Mol. Sci. 2019, 20(9), 2351; https://doi.org/10.3390/ijms20092351 - 11 May 2019

Cited by 8 | Viewed by 3237

Abstract

The human body regenerates constantly in part under the control of signaling pathways that regulate cell growth [...] Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

Research

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14 pages, 2590 KiB

Open AccessArticle

NVP-BEZ235 Attenuated Cell Proliferation and Migration in the Squamous Cell Carcinoma of Oral Cavities and p70S6K Inhibition Mimics its Effect

by Cheng-Ming Hsu, Pai-Mei Lin, Hsin-Ching Lin, Yao-Te Tsai, Ming-Shao Tsai, Shau-Hsuan Li, Ching-Yuan Wu, Yao-Hsu Yang, Sheng-Fung Lin and Ming-Yu Yang

Int. J. Mol. Sci. 2018, 19(11), 3546; https://doi.org/10.3390/ijms19113546 - 10 Nov 2018

Cited by 11 | Viewed by 3693

Abstract

NVP-BEZ235 or BEZ235 is a dual inhibitor of adenosine triphosphate (ATP)-competitive phosphoinositide 3-kinase (PI3K)/mammalian-target-of-rapamycin (mTOR) and is promising for cancer treatment. Because it targets more than one downstream effector, a dual approach is promising for cancer treatment. The aim of this study was [...] Read more.

NVP-BEZ235 or BEZ235 is a dual inhibitor of adenosine triphosphate (ATP)-competitive phosphoinositide 3-kinase (PI3K)/mammalian-target-of-rapamycin (mTOR) and is promising for cancer treatment. Because it targets more than one downstream effector, a dual approach is promising for cancer treatment. The aim of this study was to evaluate the efficacy of NVP-BEZ235 in treating oral cavity squamous cell carcinoma (OSCC). Two human OSCC cell lines, SCC-4 and SCC-25, were used in this study. PI3K-AKT signaling, proliferation, and cell migratory and invasion capabilities of OSCC cells were examined. In NVP-BEZ235-treated SCC-4 and SCC-25 cells, the phosphorylation of 70-kDa ribosomal S6 kinase (p70S6K), but not mTOR, decreased within 24 h. NVP-BEZ235 inhibited OSCC-cell proliferation, migration, and invasion possibly by directly deregulating the phosphorylation of p70S6K. The phospho-p70S6K inhibitor mimicked the effects of NVP-BEZ235 for preventing proliferation and weakening the migratory and invasion abilities of SCC-4 and SCC-25 cells. This study further confirmed the effect of NVP-BEZ235 on OSCC cells and provided a new strategy for controlling the proliferation, migration, and invasion of OSCC cells using the phopho-p70S6K inhibitor. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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13 pages, 4410 KiB

Open AccessArticle

Combined Fluid Shear Stress and Melatonin Enhances the ERK/Akt/mTOR Signal in Cilia-Less MC3T3-E1 Preosteoblast Cells

by Chi Hyun Kim, Eui-Bae Jeung and Yeong-Min Yoo

Int. J. Mol. Sci. 2018, 19(10), 2929; https://doi.org/10.3390/ijms19102929 - 26 Sep 2018

Cited by 9 | Viewed by 3689

Abstract

We investigated whether combined fluid shear stress (FSS) and melatonin stimulated signal transduction in cilia-less MC3T3-E1 preosteoblast cells. MC3T3-E1 cells were treated with chloral hydrate or nocodazole, and mechanotransduction sensor primary cilia were removed. p-extracellular signal–regulated kinase (ERK) and p-Akt with/without melatonin increased [...] Read more.

We investigated whether combined fluid shear stress (FSS) and melatonin stimulated signal transduction in cilia-less MC3T3-E1 preosteoblast cells. MC3T3-E1 cells were treated with chloral hydrate or nocodazole, and mechanotransduction sensor primary cilia were removed. p-extracellular signal–regulated kinase (ERK) and p-Akt with/without melatonin increased with nocodazole treatment and decreased with chloral hydrate treatment, whereas p-ERK and p-Akt in FSS with/without melatonin increased in cilia-less groups compared to cilia groups. Furthermore, p-mammalian target of rapamycin (mTOR) with FSS-plus melatonin increased in cilia-less groups compared to only melatonin treatments in cilia groups. Expressions of Bcl-2, Cu/Zn-superoxide dismutase (SOD), and catalase proteins were higher in FSS with/without melatonin with cilia-less groups than only melatonin treatments in cilia groups. Bax protein expression was high in FSS-plus melatonin with chloral hydrate treatment. In chloral hydrate treatment with/without FSS, expressions of Cu/Zn-SOD, Mn-SOD, and catalase proteins were high compared to only-melatonin treatments. In nocodazole treatment, Mn-SOD protein expression without FSS was high, and catalase protein level with FSS was low, compared to only melatonin treatments. These data show that the combination with FSS and melatonin enhances ERK/Akt/mTOR signal in cilia-less MC3T3-E1, and the enhanced signaling in cilia-less MC3T3-E1 osteoblast cells may activate the anabolic effect for the preservation of cell structure and function. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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16 pages, 2179 KiB

Open AccessArticle

Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway

by Jing Xu, R. Paige Mathena, Michael Xu, YuChia Wang, CheJui Chang, Yiwen Fang, Pengbo Zhang and C. David Mintz

Int. J. Mol. Sci. 2018, 19(8), 2183; https://doi.org/10.3390/ijms19082183 - 26 Jul 2018

Cited by 27 | Viewed by 4764

Abstract

Human epidemiologic studies and laboratory investigations in animal models suggest that exposure to general anesthetic agents (GAs) have harmful effects on brain development. The mechanism underlying this putative iatrogenic condition is not clear and there are currently no accepted strategies for prophylaxis or [...] Read more.

Human epidemiologic studies and laboratory investigations in animal models suggest that exposure to general anesthetic agents (GAs) have harmful effects on brain development. The mechanism underlying this putative iatrogenic condition is not clear and there are currently no accepted strategies for prophylaxis or treatment. Recent evidence suggests that anesthetics might cause persistent deficits in synaptogenesis by disrupting key events in neurodevelopment. Using an in vitro model consisting of dissociated primary cultured mouse neurons, we demonstrate abnormal pre- and post-synaptic marker expression after a clinically-relevant isoflurane anesthesia exposure is conducted during neuron development. We find that pharmacologic inhibition of the mechanistic target of rapamycin (mTOR) pathway can reverse the observed changes. Isoflurane exposure increases expression of phospho-S6, a marker of mTOR pathway activity, in a concentration-dependent fashion and this effect occurs throughout neuronal development. The mTOR 1 complex (mTORC1) and the mTOR 2 complex (mTORC2) branches of the pathway are both activated by isoflurane exposure and this is reversible with branch-specific inhibitors. Upregulation of mTOR is also seen with sevoflurane and propofol exposure, suggesting that this mechanism of developmental anesthetic neurotoxicity may occur with all the commonly used GAs in pediatric practice. We conclude that GAs disrupt the development of neurons during development by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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16 pages, 3604 KiB

Open AccessArticle

Dopamine Receptor Subtypes Differentially Regulate Autophagy

by Dongmei Wang, Xinmiao Ji, Juanjuan Liu, Zhiyuan Li and Xin Zhang

Int. J. Mol. Sci. 2018, 19(5), 1540; https://doi.org/10.3390/ijms19051540 - 22 May 2018

Cited by 34 | Viewed by 6520

Abstract

Some dopamine receptor subtypes were reported to participate in autophagy regulation, but their exact functions and mechanisms are still unclear. Here we found that dopamine receptors D2 and D3 (D2-like family) are positive regulators of autophagy, while dopamine receptors D1 and D5 (D1-like [...] Read more.

Some dopamine receptor subtypes were reported to participate in autophagy regulation, but their exact functions and mechanisms are still unclear. Here we found that dopamine receptors D2 and D3 (D2-like family) are positive regulators of autophagy, while dopamine receptors D1 and D5 (D1-like family) are negative regulators. Furthermore, dopamine and ammonia, the two reported endogenous ligands of dopamine receptors, both can induce dopamine receptor internalization and degradation. In addition, we found that AKT (protein kinase B)-mTOR (mechanistic target of rapamycin) and AMPK (AMP-activated protein kinase) pathways are involved in DRD3 (dopamine receptor D3) regulated autophagy. Moreover, autophagy machinery perturbation inhibited DRD3 degradation and increased DRD3 oligomer. Therefore, our study investigated the functions and mechanisms of dopamine receptors in autophagy regulation, which not only provides insights into better understanding of some dopamine receptor-related neurodegeneration diseases, but also sheds light on their potential treatment in combination with autophagy or mTOR pathway modulations. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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15 pages, 3132 KiB

Open AccessArticle

mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor Behavior and SLC5A5 mRNA Expression

by Catarina Tavares, Catarina Eloy, Miguel Melo, Adriana Gaspar da Rocha, Ana Pestana, Rui Batista, Luciana Bueno Ferreira, Elisabete Rios, Manuel Sobrinho Simões and Paula Soares

Int. J. Mol. Sci. 2018, 19(5), 1448; https://doi.org/10.3390/ijms19051448 - 13 May 2018

Cited by 29 | Viewed by 4466

Abstract

The mammalian target of rapamycin (mTOR) pathway is overactivated in thyroid cancer (TC). We previously demonstrated that phospho-mTOR expression is associated with tumor aggressiveness, therapy resistance, and lower mRNA expression of SLC5A5 in papillary thyroid carcinoma (PTC), while phospho-S6 (mTORC1 effector) expression was [...] Read more.

The mammalian target of rapamycin (mTOR) pathway is overactivated in thyroid cancer (TC). We previously demonstrated that phospho-mTOR expression is associated with tumor aggressiveness, therapy resistance, and lower mRNA expression of SLC5A5 in papillary thyroid carcinoma (PTC), while phospho-S6 (mTORC1 effector) expression was associated with less aggressive clinicopathological features. The distinct behavior of the two markers led us to hypothesize that mTOR activation may be contributing to a preferential activation of the mTORC2 complex. To approach this question, we performed immunohistochemistry for phospho-AKT Ser473 (mTORC2 effector) in a series of 182 PTCs previously characterized for phospho-mTOR and phospho-S6 expression. We evaluated the impact of each mTOR complex on SLC5A5 mRNA expression by treating cell lines with RAD001 (mTORC1 blocker) and Torin2 (mTORC1 and mTORC2 blocker). Phospho-AKT Ser473 expression was positively correlated with phospho-mTOR expression. Nuclear expression of phospho-AKT Ser473 was significantly associated with the presence of distant metastases. Treatment of cell lines with RAD001 did not increase SLC5A5 mRNA levels, whereas Torin2 caused a ~6 fold increase in SLC5A5 mRNA expression in the TPC1 cell line. In PTC, phospho-mTOR activation may lead to the activation of the mTORC2 complex. Its downstream effector, phospho-AKT Ser473, may be implicated in distant metastization, therapy resistance, and downregulation of SLC5A5 mRNA expression. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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22 pages, 1443 KiB

Open AccessArticle

In Vitro Identification of New Transcriptomic and miRNomic Profiles Associated with Pulmonary Fibrosis Induced by High Doses Everolimus: Looking for New Pathogenetic Markers and Therapeutic Targets

by Simona Granata, Gloria Santoro, Valentina Masola, Paola Tomei, Fabio Sallustio, Paola Pontrelli, Matteo Accetturo, Nadia Antonucci, Pierluigi Carratù, Antonio Lupo and Gianluigi Zaza

Int. J. Mol. Sci. 2018, 19(4), 1250; https://doi.org/10.3390/ijms19041250 - 20 Apr 2018

Cited by 8 | Viewed by 4773

Abstract

The administration of Everolimus (EVE), a mTOR inhibitor used in transplantation and cancer, is often associated with adverse effects including pulmonary fibrosis. Although the underlying mechanism is not fully clarified, this condition could be in part caused by epithelial to mesenchymal transition (EMT) [...] Read more.

The administration of Everolimus (EVE), a mTOR inhibitor used in transplantation and cancer, is often associated with adverse effects including pulmonary fibrosis. Although the underlying mechanism is not fully clarified, this condition could be in part caused by epithelial to mesenchymal transition (EMT) of airway cells. To improve our knowledge, primary bronchial epithelial cells (BE63/3) were treated with EVE (5 and 100 nM) for 24 h. EMT markers (α-SMA, vimentin, fibronectin) were measured by RT-PCR. Transepithelial resistance was measured by Millicell-ERS ohmmeter. mRNA and microRNA profiling were performed by Illumina and Agilent kit, respectively. Only high dose EVE increased EMT markers and reduced the transepithelial resistance of BE63/3. Bioinformatics showed 125 de-regulated genes that, according to enrichment analysis, were implicated in collagen synthesis/metabolism. Connective tissue growth factor (CTGF) was one of the higher up-regulated mRNA. Five nM EVE was ineffective on the pro-fibrotic machinery. Additionally, 3 miRNAs resulted hyper-expressed after 100 nM EVE and able to regulate 31 of the genes selected by the transcriptomic analysis (including CTGF). RT-PCR and western blot for MMP12 and CTGF validated high-throughput results. Our results revealed a complex biological network implicated in EVE-related pulmonary fibrosis and underlined new potential disease biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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18 pages, 1644 KiB

Open AccessArticle

Resistance to the Antiproliferative In Vitro Effect of PI3K-Akt-mTOR Inhibition in Primary Human Acute Myeloid Leukemia Cells Is Associated with Altered Cell Metabolism

by Ina Nepstad, Håkon Reikvam, Annette K. Brenner, Øystein Bruserud and Kimberley J. Hatfield

Int. J. Mol. Sci. 2018, 19(2), 382; https://doi.org/10.3390/ijms19020382 - 27 Jan 2018

Cited by 22 | Viewed by 4783

Abstract

Constitutive signaling through the phosphatidylinositol-3-kinase-Akt-mechanistic target of rapamycin (PI3K-Akt-mTOR) pathway is present in acute myeloid leukemia (AML) cells. However, AML is a heterogeneous disease, and we therefore investigated possible associations between cellular metabolism and sensitivity to PI3K-Akt-mTOR pathway inhibitors. We performed non-targeted metabolite [...] Read more.

Constitutive signaling through the phosphatidylinositol-3-kinase-Akt-mechanistic target of rapamycin (PI3K-Akt-mTOR) pathway is present in acute myeloid leukemia (AML) cells. However, AML is a heterogeneous disease, and we therefore investigated possible associations between cellular metabolism and sensitivity to PI3K-Akt-mTOR pathway inhibitors. We performed non-targeted metabolite profiling to compare the metabolome differences of primary human AML cells derived from patients susceptible or resistant to the in vitro antiproliferative effects of mTOR and PI3K inhibitors. In addition, the phosphorylation status of 18 proteins involved in PI3K-Akt-mTOR signaling and the effect of the cyclooxygenase inhibitor indomethacin on their phosphorylation status was investigated by flow cytometry. Strong antiproliferative effects by inhibitors were observed only for a subset of patients. We compared the metabolite profiles for responders and non-responders towards PI3K-mTOR inhibitors, and 627 metabolites could be detected. Of these metabolites, 128 were annotated and 15 of the annotated metabolites differed significantly between responders and non-responders, including metabolites involved in energy, amino acid, and lipid metabolism. To conclude, leukemia cells that are susceptible or resistant to PI3K-Akt-mTOR inhibitors differ in energy, amino acid, and arachidonic acid metabolism, and modulation of arachidonic acid metabolism alters the activation of mTOR and its downstream mediators. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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Review

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20 pages, 3261 KiB

Open AccessReview

Molecular Mechanisms Controlled by mTOR in Male Reproductive System

by Bruno P. Moreira, Pedro F. Oliveira and Marco G. Alves

Int. J. Mol. Sci. 2019, 20(7), 1633; https://doi.org/10.3390/ijms20071633 - 2 Apr 2019

Cited by 36 | Viewed by 6326

Abstract

In recent years, the mammalian target of rapamycin (mTOR) has emerged as a master integrator of upstream inputs, such as amino acids, growth factors and insulin availability, energy status and many others. The integration of these signals promotes a response through several downstream [...] Read more.

In recent years, the mammalian target of rapamycin (mTOR) has emerged as a master integrator of upstream inputs, such as amino acids, growth factors and insulin availability, energy status and many others. The integration of these signals promotes a response through several downstream effectors that regulate protein synthesis, glucose metabolism and cytoskeleton organization, among others. All these biological processes are essential for male fertility, thus it is not surprising that novel molecular mechanisms controlled by mTOR in the male reproductive tract have been described. Indeed, since the first clinical evidence showed that men taking rapamycin were infertile, several studies have evidenced distinct roles for mTOR in spermatogenesis. However, there is a lack of consensus whether mTOR inhibition, which remains the experimental approach that originates the majority of available data, has a negative or positive impact on male reproductive health. Herein we discuss the latest findings concerning mTOR activity in testes, particularly its role on spermatogonial stem cell (SSC) maintenance and differentiation, as well as in the physiology of Sertoli cells (SCs), responsible for blood–testis barrier maintenance/restructuring and the nutritional support of spermatogenesis. Taken together, these recent advances highlight a crucial role for mTOR in determining the male reproductive potential. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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19 pages, 670 KiB

Open AccessReview

Physical Activity Alleviates Cognitive Dysfunction of Alzheimer’s Disease through Regulating the mTOR Signaling Pathway

by Xianjuan Kou, Dandan Chen and Ning Chen

Int. J. Mol. Sci. 2019, 20(7), 1591; https://doi.org/10.3390/ijms20071591 - 29 Mar 2019

Cited by 39 | Viewed by 7711

Abstract

Alzheimer’s disease (AD) is one of the most common aging-related progressive neurodegenerative disorders, and can result in great suffering for a large portion of the aged population. Although the pathogenesis of AD is being elucidated, the exact mechanisms are still unclear, thereby impeding [...] Read more.

Alzheimer’s disease (AD) is one of the most common aging-related progressive neurodegenerative disorders, and can result in great suffering for a large portion of the aged population. Although the pathogenesis of AD is being elucidated, the exact mechanisms are still unclear, thereby impeding the development of effective drugs, supplements, and other interventional strategies for AD. In recent years, impaired autophagy associated with microRNA (miRNA) dysfunction has been reported to be involved in aging and aging-related neurodegenerative diseases. Therefore, miRNA-mediated regulation for the functional status of autophagy may become one of the potent interventional strategies for AD. Mounting evidence from in vivo AD models has demonstrated that physical activity can exert a neuroprotective role in AD. In addition, autophagy is strictly regulated by the mTOR signaling pathway. In this article, the regulation of the functional status of autophagy through the mTOR signaling pathway during physical activity is systematically discussed for the prevention and treatment of AD. This concept will be beneficial to developing novel and effective targets that can create a direct link between pharmacological intervention and AD in the future. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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13 pages, 2124 KiB

Open AccessReview

mTOR is a Key Protein Involved in the Metabolic Effects of Simple Sugars

by Gemma Sangüesa, Núria Roglans, Miguel Baena, Ana Magdalena Velázquez, Juan Carlos Laguna and Marta Alegret

Int. J. Mol. Sci. 2019, 20(5), 1117; https://doi.org/10.3390/ijms20051117 - 5 Mar 2019

Cited by 41 | Viewed by 8833

Abstract

One of the most important threats to global human health is the increasing incidences of metabolic pathologies (including obesity, type 2 diabetes and non-alcoholic fatty liver disease), which is paralleled by increasing consumptions of hypercaloric diets enriched in simple sugars. The challenge is [...] Read more.

One of the most important threats to global human health is the increasing incidences of metabolic pathologies (including obesity, type 2 diabetes and non-alcoholic fatty liver disease), which is paralleled by increasing consumptions of hypercaloric diets enriched in simple sugars. The challenge is to identify the metabolic pathways affected by the excessive consumption of these dietary components when they are consumed in excess, to unravel the molecular mechanisms leading to metabolic pathologies and identify novel therapeutic targets to manage them. Mechanistic (mammalian) target of rapamycin (mTOR) has emerged as one of the key molecular nodes that integrate extracellular signals, such as energy status and nutrient availability, to trigger cell responses that could lead to the above-mentioned diseases through the regulation of lipid and glucose metabolism. By activating mTOR signalling, excessive consumption of simple sugars (such as fructose and glucose), could modulate hepatic gluconeogenesis, lipogenesis and fatty acid uptake and catabolism and thus lipid deposition in the liver. In the present review we will discuss some of the most recent studies showing the central role of mTOR in the metabolic effects of excessive simple sugar consumption. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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28 pages, 2587 KiB

Open AccessReview

The Cutting Edge: The Role of mTOR Signaling in Laminopathies

by Francesca Chiarini, Camilla Evangelisti, Vittoria Cenni, Antonietta Fazio, Francesca Paganelli, Alberto M. Martelli and Giovanna Lattanzi

Int. J. Mol. Sci. 2019, 20(4), 847; https://doi.org/10.3390/ijms20040847 - 15 Feb 2019

Cited by 27 | Viewed by 6740

Abstract

The mechanistic target of rapamycin (mTOR) is a ubiquitous serine/threonine kinase that regulates anabolic and catabolic processes, in response to environmental inputs. The existence of mTOR in numerous cell compartments explains its specific ability to sense stress, execute growth signals, and regulate autophagy. [...] Read more.

The mechanistic target of rapamycin (mTOR) is a ubiquitous serine/threonine kinase that regulates anabolic and catabolic processes, in response to environmental inputs. The existence of mTOR in numerous cell compartments explains its specific ability to sense stress, execute growth signals, and regulate autophagy. mTOR signaling deregulation is closely related to aging and age-related disorders, among which progeroid laminopathies represent genetically characterized clinical entities with well-defined phenotypes. These diseases are caused by LMNA mutations and feature altered bone turnover, metabolic dysregulation, and mild to severe segmental progeria. Different LMNA mutations cause muscular, adipose tissue and nerve pathologies in the absence of major systemic involvement. This review explores recent advances on mTOR involvement in progeroid and tissue-specific laminopathies. Indeed, hyper-activation of protein kinase B (AKT)/mTOR signaling has been demonstrated in muscular laminopathies, and rescue of mTOR-regulated pathways increases lifespan in animal models of Emery-Dreifuss muscular dystrophy. Further, rapamycin, the best known mTOR inhibitor, has been used to elicit autophagy and degradation of mutated lamin A or progerin in progeroid cells. This review focuses on mTOR-dependent pathogenetic events identified in Emery-Dreifuss muscular dystrophy, LMNA-related cardiomyopathies, Hutchinson-Gilford Progeria, mandibuloacral dysplasia, and type 2 familial partial lipodystrophy. Pharmacological application of mTOR inhibitors in view of therapeutic strategies is also discussed. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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34 pages, 675 KiB

Open AccessReview

mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy

by Tian Tian, Xiaoyi Li and Jinhua Zhang

Int. J. Mol. Sci. 2019, 20(3), 755; https://doi.org/10.3390/ijms20030755 - 11 Feb 2019

Cited by 429 | Viewed by 19311

Abstract

The mammalian or mechanistic target of rapamycin (mTOR) pathway plays a crucial role in regulation of cell survival, metabolism, growth and protein synthesis in response to upstream signals in both normal physiological and pathological conditions, especially in cancer. Aberrant mTOR signaling resulting from [...] Read more.

The mammalian or mechanistic target of rapamycin (mTOR) pathway plays a crucial role in regulation of cell survival, metabolism, growth and protein synthesis in response to upstream signals in both normal physiological and pathological conditions, especially in cancer. Aberrant mTOR signaling resulting from genetic alterations from different levels of the signal cascade is commonly observed in various types of cancers. Upon hyperactivation, mTOR signaling promotes cell proliferation and metabolism that contribute to tumor initiation and progression. In addition, mTOR also negatively regulates autophagy via different ways. We discuss mTOR signaling and its key upstream and downstream factors, the specific genetic changes in the mTOR pathway and the inhibitors of mTOR applied as therapeutic strategies in eight solid tumors. Although monotherapy and combination therapy with mTOR inhibitors have been extensively applied in preclinical and clinical trials in various cancer types, innovative therapies with better efficacy and less drug resistance are still in great need, and new biomarkers and deep sequencing technologies will facilitate these mTOR targeting drugs benefit the cancer patients in personalized therapy. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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15 pages, 1072 KiB

Open AccessReview

Balancing mTOR Signaling and Autophagy in the Treatment of Parkinson’s Disease

by Zhou Zhu, Chuanbin Yang, Ashok Iyaswamy, Senthilkumar Krishnamoorthi, Sravan Gopalkrishnashetty Sreenivasmurthy, Jia Liu, Ziying Wang, Benjamin Chun-Kit Tong, Juxian Song, Jiahong Lu, King-Ho Cheung and Min Li

Int. J. Mol. Sci. 2019, 20(3), 728; https://doi.org/10.3390/ijms20030728 - 8 Feb 2019

Cited by 171 | Viewed by 13580

Abstract

The mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in regulating cell growth, proliferation, and life span. mTOR signaling is a central regulator of autophagy by modulating multiple aspects of the autophagy process, such as initiation, process, and termination through [...] Read more.

The mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in regulating cell growth, proliferation, and life span. mTOR signaling is a central regulator of autophagy by modulating multiple aspects of the autophagy process, such as initiation, process, and termination through controlling the activity of the unc51-like kinase 1 (ULK1) complex and vacuolar protein sorting 34 (VPS34) complex, and the intracellular distribution of TFEB/TFE3 and proto-lysosome tubule reformation. Parkinson’s disease (PD) is a serious, common neurodegenerative disease characterized by dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and the accumulation of Lewy bodies. An increasing amount of evidence indicates that mTOR and autophagy are critical for the pathogenesis of PD. In this review, we will summarize recent advances regarding the roles of mTOR and autophagy in PD pathogenesis and treatment. Further characterizing the dysregulation of mTOR pathway and the clinical translation of mTOR modulators in PD may offer exciting new avenues for future drug development. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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17 pages, 1009 KiB

Open AccessReview

Current Coverage of the mTOR Pathway by Next-Generation Sequencing Oncology Panels

by Rita Seeboeck, Victoria Sarne and Johannes Haybaeck

Int. J. Mol. Sci. 2019, 20(3), 690; https://doi.org/10.3390/ijms20030690 - 5 Feb 2019

Cited by 5 | Viewed by 3913

Abstract

The mTOR pathway is in the process of establishing itself as a key access-point of novel oncological drugs and targeted therapies. This is also reflected by the growing number of mTOR pathway genes included in commercially available next-generation sequencing (NGS) oncology panels. This [...] Read more.

The mTOR pathway is in the process of establishing itself as a key access-point of novel oncological drugs and targeted therapies. This is also reflected by the growing number of mTOR pathway genes included in commercially available next-generation sequencing (NGS) oncology panels. This review summarizes the portfolio of medium sized diagnostic, as well as research destined NGS panels and their coverage of the mTOR pathway, including 16 DNA-based panels and the current gene list of Foundation One as a major reference entity. In addition, we give an overview of interesting, mTOR-associated somatic mutations that are not yet incorporated. Especially eukaryotic translation initiation factors (eIFs), a group of mTOR downstream proteins, are on the rise as far as diagnostics and drug targeting in precision medicine are concerned. This review aims to raise awareness for the true coverage of NGS panels, which should be valuable in selecting the ideal platform for diagnostics and research. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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16 pages, 477 KiB

Open AccessReview

mTOR Inhibitors in Advanced Biliary Tract Cancers

by Chao-En Wu, Ming-Huang Chen and Chun-Nan Yeh

Int. J. Mol. Sci. 2019, 20(3), 500; https://doi.org/10.3390/ijms20030500 - 24 Jan 2019

Cited by 30 | Viewed by 6836

Abstract

Patients with advanced biliary tract cancers (BTCs), including cholangiocarcinoma (CCA), have poor prognosis so novel treatment is warranted for advanced BTC. In current review, we discuss the limitations of current treatment in BTC, the importance of mTOR signalling in BTC, and the possible [...] Read more.

Patients with advanced biliary tract cancers (BTCs), including cholangiocarcinoma (CCA), have poor prognosis so novel treatment is warranted for advanced BTC. In current review, we discuss the limitations of current treatment in BTC, the importance of mTOR signalling in BTC, and the possible role of mTOR inhibitors as a future treatment in BTC. Chemotherapy with gemcitabine-based chemotherapy is still the standard of care and no targeted therapy has been established in advanced BTC. PI3K/AKT/mTOR signaling pathway linking to several other pathways and networks regulates cancer proliferation and progression. Emerging evidences reveal mTOR activation is associated with tumorigenesis and drug-resistance in BTC. Rapalogs, such as sirolimus and everolimus, partially inhibit mTOR complex 1 (mTORC1) and exhibit anti-cancer activity in vitro and in vivo in BTC. Rapalogs in clinical trials demonstrate some activity in patients with advanced BTC. New-generation mTOR inhibitors against ATP-binding pocket inhibit both TORC1 and TORC2 and demonstrate more potent anti-tumor effects in vitro and in vivo, however, prospective clinical trials are warranted to prove its efficacy in patients with advanced BTC. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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15 pages, 2039 KiB

Open AccessReview

mTOR Complexes as a Nutrient Sensor for Driving Cancer Progression

by Mio Harachi, Kenta Masui, Yukinori Okamura, Ryota Tsukui, Paul S. Mischel and Noriyuki Shibata

Int. J. Mol. Sci. 2018, 19(10), 3267; https://doi.org/10.3390/ijms19103267 - 21 Oct 2018

Cited by 31 | Viewed by 7984

Abstract

Recent advancement in the field of molecular cancer research has clearly revealed that abnormality of oncogenes or tumor suppressor genes causes tumor progression thorough the promotion of intracellular metabolism. Metabolic reprogramming is one of the strategies for cancer cells to ensure their survival [...] Read more.

Recent advancement in the field of molecular cancer research has clearly revealed that abnormality of oncogenes or tumor suppressor genes causes tumor progression thorough the promotion of intracellular metabolism. Metabolic reprogramming is one of the strategies for cancer cells to ensure their survival by enabling cancer cells to obtain the macromolecular precursors and energy needed for the rapid growth. However, an orchestration of appropriate metabolic reactions for the cancer cell survival requires the precise mechanism to sense and harness the nutrient in the microenvironment. Mammalian/mechanistic target of rapamycin (mTOR) complexes are known downstream effectors of many cancer-causing mutations, which are thought to regulate cancer cell survival and growth. Recent studies demonstrate the intriguing role of mTOR to achieve the feat through metabolic reprogramming in cancer. Importantly, not only mTORC1, a well-known regulator of metabolism both in normal and cancer cell, but mTORC2, an essential partner of mTORC1 downstream of growth factor receptor signaling, controls cooperatively specific metabolism, which nominates them as an essential regulator of cancer metabolism as well as a promising candidate to garner and convey the nutrient information from the surrounding environment. In this article, we depict the recent findings on the role of mTOR complexes in cancer as a master regulator of cancer metabolism and a potential sensor of nutrients, especially focusing on glucose and amino acid sensing in cancer. Novel and detailed molecular mechanisms that amino acids activate mTOR complexes signaling have been identified. We would also like to mention the intricate crosstalk between glucose and amino acid metabolism that ensures the survival of cancer cells, but at the same time it could be exploitable for the novel intervention to target the metabolic vulnerabilities of cancer cells. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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19 pages, 1163 KiB

Open AccessReview

Role of mTOR Signaling in Tumor Microenvironment: An Overview

by Fabiana Conciatori, Chiara Bazzichetto, Italia Falcone, Sara Pilotto, Emilio Bria, Francesco Cognetti, Michele Milella and Ludovica Ciuffreda

Int. J. Mol. Sci. 2018, 19(8), 2453; https://doi.org/10.3390/ijms19082453 - 19 Aug 2018

Cited by 107 | Viewed by 7848

Abstract

The mammalian target of rapamycin (mTOR) pathway regulates major processes by integrating a variety of exogenous cues, including diverse environmental inputs in the tumor microenvironment (TME). In recent years, it has been well recognized that cancer cells co-exist and co-evolve with their TME, [...] Read more.

The mammalian target of rapamycin (mTOR) pathway regulates major processes by integrating a variety of exogenous cues, including diverse environmental inputs in the tumor microenvironment (TME). In recent years, it has been well recognized that cancer cells co-exist and co-evolve with their TME, which is often involved in drug resistance. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both the tumor immunity and angiogenesis. The activation of mTOR signaling is associated with these pro-oncogenic cellular processes, making mTOR a promising target for new combination therapies. This review highlights the role of mTOR signaling in the characterization and the activity of the TME’s elements and their implications in cancer immunotherapy. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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20 pages, 830 KiB

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Biological Aspects of mTOR in Leukemia

by Simone Mirabilii, Maria Rosaria Ricciardi, Monica Piedimonte, Valentina Gianfelici, Maria Paola Bianchi and Agostino Tafuri

Int. J. Mol. Sci. 2018, 19(8), 2396; https://doi.org/10.3390/ijms19082396 - 14 Aug 2018

Cited by 22 | Viewed by 6163

Abstract

The mammalian target of rapamycin (mTOR) is a central processor of intra- and extracellular signals, regulating many fundamental cellular processes such as metabolism, growth, proliferation, and survival. Strong evidences have indicated that mTOR dysregulation is deeply implicated in leukemogenesis. This has led to [...] Read more.

The mammalian target of rapamycin (mTOR) is a central processor of intra- and extracellular signals, regulating many fundamental cellular processes such as metabolism, growth, proliferation, and survival. Strong evidences have indicated that mTOR dysregulation is deeply implicated in leukemogenesis. This has led to growing interest in the development of modulators of its activity for leukemia treatment. This review intends to provide an outline of the principal biological and molecular functions of mTOR. We summarize the current understanding of how mTOR interacts with microRNAs, with components of cell metabolism, and with controllers of apoptotic machinery. Lastly, from a clinical/translational perspective, we recapitulate the therapeutic results in leukemia, obtained by using mTOR inhibitors as single agents and in combination with other compounds. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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33 pages, 711 KiB

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mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

by Hannah E. Walters and Lynne S. Cox

Int. J. Mol. Sci. 2018, 19(8), 2325; https://doi.org/10.3390/ijms19082325 - 8 Aug 2018

Cited by 68 | Viewed by 9398

Abstract

Chronological age represents the greatest risk factor for many life-threatening diseases, including neurodegeneration, cancer, and cardiovascular disease; ageing also increases susceptibility to infectious disease. Current efforts to tackle individual diseases may have little impact on the overall healthspan of older individuals, who would [...] Read more.

Chronological age represents the greatest risk factor for many life-threatening diseases, including neurodegeneration, cancer, and cardiovascular disease; ageing also increases susceptibility to infectious disease. Current efforts to tackle individual diseases may have little impact on the overall healthspan of older individuals, who would still be vulnerable to other age-related pathologies. However, recent progress in ageing research has highlighted the accumulation of senescent cells with chronological age as a probable underlying cause of pathological ageing. Cellular senescence is an essentially irreversible proliferation arrest mechanism that has important roles in development, wound healing, and preventing cancer, but it may limit tissue function and cause widespread inflammation with age. The serine/threonine kinase mTOR (mechanistic target of rapamycin) is a regulatory nexus that is heavily implicated in both ageing and senescence. Excitingly, a growing body of research has highlighted rapamycin and other mTOR inhibitors as promising treatments for a broad spectrum of age-related pathologies, including neurodegeneration, cancer, immunosenescence, osteoporosis, rheumatoid arthritis, age-related blindness, diabetic nephropathy, muscular dystrophy, and cardiovascular disease. In this review, we assess the use of mTOR inhibitors to treat age-related pathologies, discuss possible molecular mechanisms of action where evidence is available, and consider strategies to minimize undesirable side effects. We also emphasize the urgent need for reliable, non-invasive biomarkers of senescence and biological ageing to better monitor the efficacy of any healthy ageing therapy. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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29 pages, 1543 KiB

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mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

by Larisa Ryskalin, Fiona Limanaqi, Alessandro Frati, Carla L. Busceti and Francesco Fornai

Int. J. Mol. Sci. 2018, 19(8), 2226; https://doi.org/10.3390/ijms19082226 - 30 Jul 2018

Cited by 82 | Viewed by 9355

Abstract

The mammalian target of rapamycin (mTOR) is an ubiquitously expressed serine-threonine kinase, which senses and integrates several intracellular and environmental cues to orchestrate major processes such as cell growth and metabolism. Altered mTOR signalling is associated with brain malformation and neurological disorders. Emerging [...] Read more.

The mammalian target of rapamycin (mTOR) is an ubiquitously expressed serine-threonine kinase, which senses and integrates several intracellular and environmental cues to orchestrate major processes such as cell growth and metabolism. Altered mTOR signalling is associated with brain malformation and neurological disorders. Emerging evidence indicates that even subtle defects in the mTOR pathway may produce severe effects, which are evident as neurological and psychiatric disorders. On the other hand, administration of mTOR inhibitors may be beneficial for a variety of neuropsychiatric alterations encompassing neurodegeneration, brain tumors, brain ischemia, epilepsy, autism, mood disorders, drugs of abuse, and schizophrenia. mTOR has been widely implicated in synaptic plasticity and autophagy activation. This review addresses the role of mTOR-dependent autophagy dysfunction in a variety of neuropsychiatric disorders, to focus mainly on psychiatric syndromes including schizophrenia and drug addiction. For instance, amphetamines-induced addiction fairly overlaps with some neuropsychiatric disorders including neurodegeneration and schizophrenia. For this reason, in the present review, a special emphasis is placed on the role of mTOR on methamphetamine-induced brain alterations. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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17 pages, 2121 KiB

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mTOR and Tumor Cachexia

by Adrian P. Duval, Cheryl Jeanneret, Tania Santoro and Olivier Dormond

Int. J. Mol. Sci. 2018, 19(8), 2225; https://doi.org/10.3390/ijms19082225 - 30 Jul 2018

Cited by 26 | Viewed by 8958

Abstract

Cancer cachexia affects most patients with advanced forms of cancers. It is mainly characterized by weight loss, due to muscle and adipose mass depletion. As cachexia is associated with increased morbidity and mortality in cancer patients, identifying the underlying mechanisms leading to cachexia [...] Read more.

Cancer cachexia affects most patients with advanced forms of cancers. It is mainly characterized by weight loss, due to muscle and adipose mass depletion. As cachexia is associated with increased morbidity and mortality in cancer patients, identifying the underlying mechanisms leading to cachexia is essential in order to design novel therapeutic strategies. The mechanistic target of rapamycin (mTOR) is a major intracellular signalling intermediary that participates in cell growth by upregulating anabolic processes such as protein and lipid synthesis. Accordingly, emerging evidence suggests that mTOR and mTOR inhibitors influence cancer cachexia. Here, we review the role of mTOR in cellular processes involved in cancer cachexia and highlight the studies supporting the contribution of mTOR in cancer cachexia. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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14 pages, 491 KiB

Open AccessReview

Role of mTOR in Glucose and Lipid Metabolism

by Zhuo Mao and Weizhen Zhang

Int. J. Mol. Sci. 2018, 19(7), 2043; https://doi.org/10.3390/ijms19072043 - 13 Jul 2018

Cited by 199 | Viewed by 18517

Abstract

The mammalian target of rapamycin, mTOR is the master regulator of a cell’s growth and metabolic state in response to nutrients, growth factors and many extracellular cues. Its dysregulation leads to a number of metabolic pathological conditions, including obesity and type 2 diabetes. [...] Read more.

The mammalian target of rapamycin, mTOR is the master regulator of a cell’s growth and metabolic state in response to nutrients, growth factors and many extracellular cues. Its dysregulation leads to a number of metabolic pathological conditions, including obesity and type 2 diabetes. Here, we review recent findings on the role of mTOR in major metabolic organs, such as adipose tissues, liver, muscle, pancreas and brain. And their potentials as the mTOR related pharmacological targets will be also discussed. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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24 pages, 757 KiB

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Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update

by Camilla Evangelisti, Francesca Chiarini, James A. McCubrey and Alberto M. Martelli

Int. J. Mol. Sci. 2018, 19(7), 1878; https://doi.org/10.3390/ijms19071878 - 26 Jun 2018

Cited by 39 | Viewed by 5296

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood malignancy that arises from the clonal expansion of transformed T-cell precursors. Although T-ALL prognosis has significantly improved due to the development of intensive chemotherapeutic protocols, primary drug-resistant and relapsed patients still display a dismal [...] Read more.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood malignancy that arises from the clonal expansion of transformed T-cell precursors. Although T-ALL prognosis has significantly improved due to the development of intensive chemotherapeutic protocols, primary drug-resistant and relapsed patients still display a dismal outcome. In addition, lifelong irreversible late effects from conventional therapy are a growing problem for leukemia survivors. Therefore, novel targeted therapies are required to improve the prognosis of high-risk patients. The mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct multiprotein complexes, which are referred to as mTOR complex 1 (mTORC1) and mTORC2. These two complexes regulate a variety of physiological cellular processes including protein, lipid, and nucleotide synthesis, as well as autophagy in response to external cues. However, mTOR activity is frequently deregulated in cancer, where it plays a key oncogenetic role driving tumor cell proliferation, survival, metabolic transformation, and metastatic potential. Promising preclinical studies using mTOR inhibitors have demonstrated efficacy in many human cancer types, including T-ALL. Here, we highlight our current knowledge of mTOR signaling and inhibitors in T-ALL, with an emphasis on emerging evidence of the superior efficacy of combinations consisting of mTOR inhibitors and either traditional or targeted therapeutics. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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18 pages, 1071 KiB

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Targeting mTOR as a Therapeutic Approach in Medulloblastoma

by Juncal Aldaregia, Ainitze Odriozola, Ander Matheu and Idoia Garcia

Int. J. Mol. Sci. 2018, 19(7), 1838; https://doi.org/10.3390/ijms19071838 - 22 Jun 2018

Cited by 14 | Viewed by 5536

Abstract

Mechanistic target of rapamycin (mTOR) is a master signaling pathway that regulates organismal growth and homeostasis, because of its implication in protein and lipid synthesis, and in the control of the cell cycle and the cellular metabolism. Moreover, it is necessary in cerebellar [...] Read more.

Mechanistic target of rapamycin (mTOR) is a master signaling pathway that regulates organismal growth and homeostasis, because of its implication in protein and lipid synthesis, and in the control of the cell cycle and the cellular metabolism. Moreover, it is necessary in cerebellar development and stem cell pluripotency maintenance. Its deregulation has been implicated in the medulloblastoma and in medulloblastoma stem cells (MBSCs). Medulloblastoma is the most common malignant solid tumor in childhood. The current therapies have improved the overall survival but they carry serious side effects, such as permanent neurological sequelae and disability. Recent studies have given rise to a new molecular classification of the subgroups of medulloblastoma, specifying 12 different subtypes containing novel potential therapeutic targets. In this review we propose the targeting of mTOR, in combination with current therapies, as a promising novel therapeutic approach. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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