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mTOR Signaling Network in Cell Biology and Human Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 51476

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Special Issue Editors

Dr. Elena A. Goncharova

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Guest Editor

1. University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
2. Affiliation after August 1st 2020, University of California, Davis, Davis, CA, USA
Interests: Dr. Goncharova’s research interests have focused on the molecular and cellular mechanisms regulating cellular energy metabolism, proliferation, motility, and survival as they relate to the pathogenesis of pulmonary arterial hypertension (PAH). Her current work specifically focuses on the role of mTOR and HIPPO signaling networks in metabolism, proliferation, survival, and phenotype switching of pulmonary vascular cells in PAH.

Dr. Jane J. Yu

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Co-Guest Editor

Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA
Interests: rare lung diseases; Lymphangioleiomyomatosis (LAM); tuberous sclerosis complex (TSC); steroid hormone biology; mTOR signaling; cell metabolism;cancer metastasis; preclinical imaging

Special Issue Information

Dear Colleagues,

The mechanistic target of rapamycin (mTOR) is a key regulator of cell homeostasis in response to environmental stimuli. Acting via two functionally different complexes, mTORC1 and mTORC2, this serine-threonine protein kinase regulates key aspects of cellular and organismal behavior. Not surprisingly, deregulation of mTOR is involved in numerous human diseases and conditions, including cancer, cardiovascular disease, metabolic diseases, and ageing.

This Special Issue is focused on the mechanisms of regulation and function of mTOR in cellular biology, normal physiology, and disease, as well as on the preclinical and clinical research exploring mTOR as a molecular target for therapeutic intervention to treat various diseases and conditions and/or combat ageing.

Dr. Elena A. Goncharova
Guest Editor
Dr. Jane J. Yu
Co-Guest Editor

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Keywords

mTOR
mTORC1
mTORC2
cell biology
cell metabolism
cancer
diabetes
cardiovascular disease
ageing

Published Papers (14 papers)

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Editorial

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6 pages, 226 KiB

Open AccessEditorial

mTOR Signaling Network in Cell Biology and Human Disease

by Jane J. Yu and Elena A. Goncharova

Int. J. Mol. Sci. 2022, 23(24), 16142; https://doi.org/10.3390/ijms232416142 - 18 Dec 2022

Cited by 8 | Viewed by 1818

Abstract

The mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that regulates multiple processes, including gene transcription, protein synthesis, ribosome biogenesis, autophagy, cell metabolism, and cell growth [...] Full article

(This article belongs to the Special Issue mTOR Signaling Network in Cell Biology and Human Disease)

Research

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15 pages, 4389 KiB

Open AccessArticle

Sirolimus Suppresses Phosphorylation of Cofilin and Reduces Interstitial Septal Thickness in Sporadic Lymphangioleiomyomatosis

by Yen-Lin Huang, Po-Ru Chen, Ying-Ju Lai and Hsao-Hsun Hsu

Int. J. Mol. Sci. 2021, 22(16), 8564; https://doi.org/10.3390/ijms22168564 - 9 Aug 2021

Cited by 1 | Viewed by 2635

Abstract

Sporadic lymphangioleiomyomatosis (S-LAM) is a rare lung disease characterized by the proliferation of smooth muscle-like LAM cells and progressive cystic destruction. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has a proven efficacy in patients with LAM. However, the therapeutic mechanisms of sirolimus in LAM remain unclear. We aimed to evaluate sirolimus-related lung parenchymal changes and the potential effect in LAM cells and modulating pathological cystic destruction. Lung specimens were examined for histopathological changes by HMB45 staining and compared the LAM patients treated with and without sirolimus. We detected the overexpression of mTOR, HMB45, and phosphorylation of cofilin (p-cofilin) in LAM patients. Sirolimus showed efficacy in patients with LAM, who exhibited a reduced expression of mTOR and p-cofilin as well as reduced interstitial septal thickness. In addition, sirolimus suppresses mTOR and p-cofilin, thus suppressing the migration and proliferation of LAM cells isolated from the patient’s lung tissue. This study demonstrates that interstitial septal thickness, as determined by histological structural analysis. Sirolimus effectively reduced the expression of p-cofilin and interstitial septal thickness, which may be a novel mechanism by sirolimus. Moreover, we develop a new method to isolate and culture the LAM cell, which can test the possibility of medication in vitro and impact this current study has on the LAM field. The development of approaches to interfere with mTOR-cofilin1-actin signaling may result in an option for S-LAM therapy. Full article

(This article belongs to the Special Issue mTOR Signaling Network in Cell Biology and Human Disease)

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12 pages, 4788 KiB

Open AccessArticle

The mTORC2 Regulator Homer1 Modulates Protein Levels and Sub-Cellular Localization of the CaSR in Osteoblast-Lineage Cells

by Mark S. Rybchyn, Tara Clare Brennan-Speranza, David Mor, Zhiqiang Cheng, Wenhan Chang, Arthur D. Conigrave and Rebecca S. Mason

Int. J. Mol. Sci. 2021, 22(12), 6509; https://doi.org/10.3390/ijms22126509 - 17 Jun 2021

Cited by 7 | Viewed by 2408

Abstract

We recently found that, in human osteoblasts, Homer1 complexes to Calcium-sensing receptor (CaSR) and mediates AKT initiation via mechanistic target of rapamycin complex (mTOR) complex 2 (mTORC2) leading to beneficial effects in osteoblasts including β-catenin stabilization and mTOR complex 1 (mTORC1) activation. Herein we further investigated the relationship between Homer1 and CaSR and demonstrate a link between the protein levels of CaSR and Homer1 in human osteoblasts in primary culture. Thus, when siRNA was used to suppress the CaSR, we observed upregulated Homer1 levels, and when siRNA was used to suppress Homer1 we observed downregulated CaSR protein levels using immunofluorescence staining of cultured osteoblasts as well as Western blot analyses of cell protein extracts. This finding was confirmed in vivo as the bone cells from osteoblast specific CaSR−/− mice showed increased Homer1 expression compared to wild-type (wt). CaSR and Homer1 protein were both expressed in osteocytes embedded in the long bones of wt mice, and immunofluorescent studies of these cells revealed that Homer1 protein sub-cellular localization was markedly altered in the osteocytes of CaSR−/− mice compared to wt. The study identifies additional roles for Homer1 in the control of the protein level and subcellular localization of CaSR in cells of the osteoblast lineage, in addition to its established role of mTORC2 activation downstream of the receptor. Full article

(This article belongs to the Special Issue mTOR Signaling Network in Cell Biology and Human Disease)

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15 pages, 18041 KiB

Open AccessArticle

Yes-Associated Protein (Yap) Is Up-Regulated in Heart Failure and Promotes Cardiac Fibroblast Proliferation

by Maryam Sharifi-Sanjani, Mariah Berman, Dmitry Goncharov, Mohammad Alhamaydeh, Theodore Guy Avolio, Jeffrey Baust, Baojun Chang, Ahasanul Kobir, Mark Ross, Claudette St. Croix, Seyed Mehdi Nouraie, Charles F. McTiernan, Christine S. Moravec, Elena Goncharova and Imad Al Ghouleh

Int. J. Mol. Sci. 2021, 22(11), 6164; https://doi.org/10.3390/ijms22116164 - 7 Jun 2021

Cited by 12 | Viewed by 3805

Abstract

Left ventricular (LV) heart failure (HF) is a significant and increasing cause of death worldwide. HF is characterized by myocardial remodeling and excessive fibrosis. Transcriptional co-activator Yes-associated protein (Yap), the downstream effector of HIPPO signaling pathway, is an essential factor in cardiomyocyte survival; however, its status in human LV HF is not entirely elucidated. Here, we report that Yap is elevated in LV tissue of patients with HF, and is associated with down-regulation of its upstream inhibitor HIPPO component large tumor suppressor 1 (LATS1) activation as well as upregulation of the fibrosis marker connective tissue growth factor (CTGF). Applying the established profibrotic combined stress of TGFβ and hypoxia to human ventricular cardiac fibroblasts in vitro increased Yap protein levels, down-regulated LATS1 activation, increased cell proliferation and collagen I production, and decreased ribosomal protein S6 and S6 kinase phosphorylation, a hallmark of mTOR activation, without any significant effect on mTOR and raptor protein expression or phosphorylation of mTOR or 4E-binding protein 1 (4EBP1), a downstream effector of mTOR pathway. As previously reported in various cell types, TGFβ/hypoxia also enhanced cardiac fibroblast Akt and ERK1/2 phosphorylation, which was similar to our observation in LV tissues from HF patients. Further, depletion of Yap reduced TGFβ/hypoxia-induced cardiac fibroblast proliferation and Akt phosphorylation at Ser 473 and Thr308, without any significant effect on TGFβ/hypoxia-induced ERK1/2 activation or reduction in S6 and S6 kinase activities. Taken together, these data demonstrate that Yap is a mediator that promotes human cardiac fibroblast proliferation and suggest its possible contribution to remodeling of the LV, opening the door to further studies to decipher the cell-specific roles of Yap signaling in human HF. Full article

(This article belongs to the Special Issue mTOR Signaling Network in Cell Biology and Human Disease)

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12 pages, 2361 KiB

Open AccessArticle

Do Autism Spectrum and Autoimmune Disorders Share Predisposition Gene Signature Due to mTOR Signaling Pathway Controlling Expression?

by Ekaterina A. Trifonova, Alexandra I. Klimenko, Zakhar S. Mustafin, Sergey A. Lashin and Alex V. Kochetov

Int. J. Mol. Sci. 2021, 22(10), 5248; https://doi.org/10.3390/ijms22105248 - 16 May 2021

Cited by 9 | Viewed by 3388

Abstract

Autism spectrum disorder (ASD) is characterized by uncommon genetic heterogeneity and a high heritability concurrently. Most autoimmune disorders (AID), similarly to ASD, are characterized by impressive genetic heterogeneity and heritability. We conducted gene-set analyses and revealed that 584 out of 992 genes (59%) included in a new release of the SFARI Gene database and 439 out of 871 AID-associated genes (50%) could be attributed to one of four groups: 1. FMRP (fragile X mental retardation protein) target genes, 2. mTOR signaling network genes, 3. mTOR-modulated genes, and 4. vitamin D3-sensitive genes. With the exception of FMRP targets, which are obviously associated with the direct involvement of local translation disturbance in the pathological mechanisms of ASD, the remaining categories are represented among AID genes in a very similar percentage as among ASD predisposition genes. Thus, mTOR signaling pathway genes make up 4% of ASD and 3% of AID genes, mTOR-modulated genes—31% of both ASD and AID genes, and vitamin D-sensitive genes—20% of ASD and 23% of AID genes. The network analysis revealed 3124 interactions between 528 out of 729 AID genes for the 0.7 cutoff, so the great majority (up to 67%) of AID genes are related to the mTOR signaling pathway directly or indirectly. Our present research and available published data allow us to hypothesize that both a certain part of ASD and AID comprise a connected set of disorders sharing a common aberrant pathway (mTOR signaling) rather than a vast set of different disorders. Furthermore, an immune subtype of the autism spectrum might be a specific type of autoimmune disorder with an early manifestation of a unique set of predominantly behavioral symptoms. Full article

(This article belongs to the Special Issue mTOR Signaling Network in Cell Biology and Human Disease)

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14 pages, 2968 KiB

Open AccessArticle

Connectivity Map Analysis of a Single-Cell RNA-Sequencing -Derived Transcriptional Signature of mTOR Signaling

by Naim Al Mahi, Erik Y. Zhang, Susan Sherman, Jane J. Yu and Mario Medvedovic

Int. J. Mol. Sci. 2021, 22(9), 4371; https://doi.org/10.3390/ijms22094371 - 22 Apr 2021

Cited by 8 | Viewed by 3695

Abstract

In the connectivity map (CMap) approach to drug repositioning and development, transcriptional signature of disease is constructed by differential gene expression analysis between the diseased tissue or cells and the control. The negative correlation between the transcriptional disease signature and the transcriptional signature of the drug, or a bioactive compound, is assumed to indicate its ability to “reverse” the disease process. A major limitation of traditional CMaP analysis is the use of signatures derived from bulk disease tissues. Since the key driver pathways are most likely dysregulated in only a subset of cells, the “averaged” transcriptional signatures resulting from bulk analysis lack the resolution to effectively identify effective therapeutic agents. The use of single-cell RNA-seq (scRNA-seq) transcriptomic assay facilitates construction of disease signatures that are specific to individual cell types, but methods for using scRNA-seq data in the context of CMaP analysis are lacking. Lymphangioleiomyomatosis (LAM) mutations in TSC1 or TSC2 genes result in the activation of the mTOR complex 1 (mTORC1). The mTORC1 inhibitor Sirolimus is the only FDA-approved drug to treat LAM. Novel therapies for LAM are urgently needed as the disease recurs with discontinuation of the treatment and some patients are insensitive to the drug. We developed methods for constructing disease transcriptional signatures and CMaP analysis using scRNA-seq profiling and applied them in the analysis of scRNA-seq data of lung tissue from naïve and sirolimus-treated LAM patients. New methods successfully implicated mTORC1 inhibitors, including Sirolimus, as capable of reverting the LAM transcriptional signatures. The CMaP analysis mimicking standard bulk-tissue approach failed to detect any connection between the LAM signature and mTORC1 signaling. This indicates that the precise signature derived from scRNA-seq data using our methods is the crucial difference between the success and the failure to identify effective therapeutic treatments in CMaP analysis. Full article

(This article belongs to the Special Issue mTOR Signaling Network in Cell Biology and Human Disease)

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16 pages, 12195 KiB

Open AccessArticle

The Characterization of a Subependymal Giant Astrocytoma-Like Cell Line from Murine Astrocyte with mTORC1 Hyperactivation

by Xin Tang, Gabrielle Angst, Michael Haas, Fuchun Yang and Chenran Wang

Int. J. Mol. Sci. 2021, 22(8), 4116; https://doi.org/10.3390/ijms22084116 - 16 Apr 2021

Cited by 3 | Viewed by 2447

Abstract

Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivating mutations in TSC1 (hamartin) or TSC2 (tuberin), crucial negative regulators of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. TSC affects multiple organs including the brain. The neurologic manifestation is characterized by cortical tubers, subependymal nodules (SEN), and subependymal giant cell astrocytoma (SEGA) in brain. SEGAs may result in hydrocephalus in TSC patients and mTORC1 inhibitors are the current recommended therapy for SEGA. Nevertheless, a major limitation in the research for SEGA is the lack of cell lines or animal models for mechanistic investigations and development of novel therapy. In this study, we generated TSC1-deficient neural cells from spontaneously immortalized mouse astrocytes in an attempt to mimic human SEGA. The TSC1-deficient cells exhibit mTORC1 hyperactivation and characteristics of transition from astrocytes to neural stem/progenitor cell phenotypes. Rapamycin efficiently decreased mTORC1 activity of these TSC1-deficient cells in vitro. In vivo, TSC1-deficient cells could form SEGA-like tumors and Rapamycin treatment decreased tumor growth. Collectively, our study generates a novel SEGA-like cell line that is invaluable for studying mTORC1-driven molecular and pathological alterations in neurologic tissue. These SEGA-like cells also provide opportunities for the development of novel therapeutic strategy for TSC patients with SEGA. Full article

(This article belongs to the Special Issue mTOR Signaling Network in Cell Biology and Human Disease)

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15 pages, 3849 KiB

Open AccessArticle

Aromadendrin Protects Neuronal Cells from Methamphetamine-Induced Neurotoxicity by Regulating Endoplasmic Reticulum Stress and PI3K/Akt/mTOR Signaling Pathway

by Hyun-Su Lee, Eun-Nam Kim and Gil-Saeng Jeong

Int. J. Mol. Sci. 2021, 22(5), 2274; https://doi.org/10.3390/ijms22052274 - 25 Feb 2021

Cited by 20 | Viewed by 2332

Abstract

Methamphetamine (METH) is a highly addictive drug that induces irreversible damage to neuronal cells and pathological malfunction in the brain. Aromadendrin, isolated from the flowers of Chionanthus retusus, has been shown to have anti-inflammatory or anti-tumor activity. Nevertheless, it has been reported that METH exacerbates neurotoxicity by inducing endoplasmic reticulum (ER) stress via the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in neuronal cells. There is little evidence that aromadendrin protects cells from neurotoxicity induced by METH. In this study, we found that aromadendrin partially suppressed the METH-induced cell death in SH-SY5y cells without causing cytotoxicity. Aromadendrin regulated METH-induced ER stress by preserving the phosphorylation of the PI3K/Akt/mTOR signaling pathway in METH-exposed SH-SY5y cells. In addition, aromadendrin mitigated METH-induced autophagic and the apoptotic pathways in METH-exposed SH-SY5y cells. Mechanistic studies revealed that pre-treatment with aromadendrin restored the expression of anti-apoptotic proteins in METH-exposed conditions. The inhibitor assay confirmed that aromadendrin-mediated restoration of mTOR phosphorylation protected cells from autophagy and apoptosis in METH-exposed cells. Therefore, these findings suggest that aromadendrin relatively has a protective effect on SH-SY5y cells against autophagy and apoptosis induced by METH via regulation of ER stress and the PI3K/Akt/mTOR signaling pathway. Full article

(This article belongs to the Special Issue mTOR Signaling Network in Cell Biology and Human Disease)

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12 pages, 2004 KiB

Open AccessArticle

HIV-1 Tat Activates Akt/mTORC1 Pathway and AICDA Expression by Downregulating Its Transcriptional Inhibitors in B Cells

by Burkitkan Akbay, Diego Germini, Amangeldy K. Bissenbaev, Yana R. Musinova, Evgeny V. Sheval, Yegor Vassetzky and Svetlana Dokudovskaya

Int. J. Mol. Sci. 2021, 22(4), 1588; https://doi.org/10.3390/ijms22041588 - 4 Feb 2021

Cited by 6 | Viewed by 2843

Abstract

HIV-1 infects T cells, but the most frequent AIDS-related lymphomas are of B-cell origin. Molecular mechanisms of HIV-1-induced oncogenic transformation of B cells remain largely unknown. HIV-1 Tat protein may participate in this process by penetrating and regulating gene expression in B cells. Both immune and cancer cells can reprogram communications between extracellular signals and intracellular signaling pathways via the Akt/mTORC1 pathway, which plays a key role in the cellular response to various stimuli including viral infection. Here, we investigated the role of HIV-1 Tat on the modulation of the Akt/mTORC1 pathway in B cells. We found that HIV-1 Tat activated the Akt/mTORC1 signaling pathway; this leads to aberrant activation of activation-induced cytidine deaminase (AICDA) due to inhibition of the AICDA transcriptional repressors c-Myb and E2F8. These perturbations may ultimately lead to an increased genomic instability and proliferation that might cause B cell malignancies. Full article

(This article belongs to the Special Issue mTOR Signaling Network in Cell Biology and Human Disease)

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16 pages, 4768 KiB

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Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma

by Jessica Guenzle, Harue Akasaka, Katharina Joechle, Wilfried Reichardt, Aina Venkatasamy, Jens Hoeppner, Claus Hellerbrand, Stefan Fichtner-Feigl and Sven A. Lang

Int. J. Mol. Sci. 2021, 22(1), 30; https://doi.org/10.3390/ijms22010030 - 22 Dec 2020

Cited by 19 | Viewed by 3795

Abstract

Despite recent advances in therapy, liver metastasis from melanoma is still associated with poor prognosis. Although targeting the mTOR signaling pathway exerts potent anti-tumor activity, little is known about specific mTORC2 inhibition regarding liver metastasis. Using the novel mTORC2 specific inhibitor JR-AB2-011, we show significantly reduced migration and invasion capacity by impaired activation of MMP2 in melanoma cells. In addition, blockade of mTORC2 induces cell death by non-apoptotic pathways and reduces tumor cell proliferation rate dose-dependently. Furthermore, a significant reduction of liver metastasis was detected in a syngeneic murine metastasis model upon therapy with JR-AB2-011 as determined by in vivo imaging and necropsy. Hence, our study for the first time highlights the impact of the pharmacological blockade of mTORC2 as a potent novel anti-cancer approach for liver metastasis from melanoma. Full article

(This article belongs to the Special Issue mTOR Signaling Network in Cell Biology and Human Disease)

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Review

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15 pages, 1559 KiB

Open AccessReview

CrossTORC and WNTegration in Disease: Focus on Lymphangioleiomyomatosis

by Jilly Frances Evans, Kseniya Obraztsova, Susan M. Lin and Vera P. Krymskaya

Int. J. Mol. Sci. 2021, 22(5), 2233; https://doi.org/10.3390/ijms22052233 - 24 Feb 2021

Cited by 7 | Viewed by 2744

Abstract

The mechanistic target of rapamycin (mTOR) and wingless-related integration site (Wnt) signal transduction networks are evolutionarily conserved mammalian growth and cellular development networks. Most cells express many of the proteins in both pathways, and this review will briefly describe only the key proteins and their intra- and extracellular crosstalk. These complex interactions will be discussed in relation to cancer development, drug resistance, and stem cell exhaustion. This review will also highlight the tumor-suppressive tuberous sclerosis complex (TSC) mutated, mTOR-hyperactive lung disease of women, lymphangioleiomyomatosis (LAM). We will summarize recent advances in the targeting of these pathways by monotherapy or combination therapy, as well as future potential treatments. Full article

(This article belongs to the Special Issue mTOR Signaling Network in Cell Biology and Human Disease)

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28 pages, 1245 KiB

Open AccessReview

mTOR Signaling in Pulmonary Vascular Disease: Pathogenic Role and Therapeutic Target

by Aleksandra Babicheva, Ayako Makino and Jason X.-J. Yuan

Int. J. Mol. Sci. 2021, 22(4), 2144; https://doi.org/10.3390/ijms22042144 - 21 Feb 2021

Cited by 29 | Viewed by 3932

Abstract

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease without a cure. The exact pathogenic mechanisms of PAH are complex and poorly understood, yet a number of abnormally expressed genes and regulatory pathways contribute to sustained vasoconstriction and vascular remodeling of the distal pulmonary arteries. Mammalian target of rapamycin (mTOR) is one of the major signaling pathways implicated in regulating cell proliferation, migration, differentiation, and protein synthesis. Here we will describe the canonical mTOR pathway, structural and functional differences between mTOR complexes 1 and 2, as well as the crosstalk with other important signaling cascades in the development of PAH. The pathogenic role of mTOR in pulmonary vascular remodeling and sustained vasoconstriction due to its contribution to proliferation, migration, phenotypic transition, and gene regulation in pulmonary artery smooth muscle and endothelial cells will be discussed. Despite the progress in our elucidation of the etiology and pathogenesis of PAH over the two last decades, there is a lack of effective therapeutic agents to treat PAH patients representing a significant unmet clinical need. In this review, we will explore the possibility and therapeutic potential to use inhibitors of mTOR signaling cascade to treat PAH. Full article

(This article belongs to the Special Issue mTOR Signaling Network in Cell Biology and Human Disease)

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28 pages, 1519 KiB

Open AccessReview

The Roles of Post-Translational Modifications on mTOR Signaling

by Shasha Yin, Liu Liu and Wenjian Gan

Int. J. Mol. Sci. 2021, 22(4), 1784; https://doi.org/10.3390/ijms22041784 - 11 Feb 2021

Cited by 20 | Viewed by 4478

Abstract

The mechanistic target of rapamycin (mTOR) is a master regulator of cell growth, proliferation, and metabolism by integrating various environmental inputs including growth factors, nutrients, and energy, among others. mTOR signaling has been demonstrated to control almost all fundamental cellular processes, such as nucleotide, protein and lipid synthesis, autophagy, and apoptosis. Over the past fifteen years, mapping the network of the mTOR pathway has dramatically advanced our understanding of its upstream and downstream signaling. Dysregulation of the mTOR pathway is frequently associated with a variety of human diseases, such as cancers, metabolic diseases, and cardiovascular and neurodegenerative disorders. Besides genetic alterations, aberrancies in post-translational modifications (PTMs) of the mTOR components are the major causes of the aberrant mTOR signaling in a number of pathologies. In this review, we summarize current understanding of PTMs-mediated regulation of mTOR signaling, and also update the progress on targeting the mTOR pathway and PTM-related enzymes for treatment of human diseases. Full article

(This article belongs to the Special Issue mTOR Signaling Network in Cell Biology and Human Disease)

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27 pages, 1234 KiB

Open AccessReview

The Role of mTOR Signaling as a Therapeutic Target in Cancer

by Nadezhda V. Popova and Manfred Jücker

Int. J. Mol. Sci. 2021, 22(4), 1743; https://doi.org/10.3390/ijms22041743 - 9 Feb 2021

Cited by 138 | Viewed by 9807

Abstract

The aim of this review was to summarize current available information about the role of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling in cancer as a potential target for new therapy options. The mTOR and PI3K/AKT/mTORC1 (mTOR complex 1) signaling are critical for the regulation of many fundamental cell processes including protein synthesis, cell growth, metabolism, survival, catabolism, and autophagy, and deregulated mTOR signaling is implicated in cancer, metabolic dysregulation, and the aging process. In this review, we summarize the information about the structure and function of the mTOR pathway and discuss the mechanisms of its deregulation in human cancers including genetic alterations of PI3K/AKT/mTOR pathway components. We also present recent data regarding the PI3K/AKT/mTOR inhibitors in clinical studies and the treatment of cancer, as well the attendant problems of resistance and adverse effects. Full article

(This article belongs to the Special Issue mTOR Signaling Network in Cell Biology and Human Disease)

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