mTOR Signaling at the Crossroad between Metazoan Regeneration and Human Diseases

A major challenge in medical research resides in controlling the molecular processes of tissue regeneration, as organ and structure damage are central to several human diseases. A survey of the literature reveals that mTOR (mechanistic/mammalian target of rapamycin) is involved in a wide range of regeneration mechanisms in the animal kingdom. More particularly, cellular processes such as growth, proliferation, and differentiation are controlled by mTOR. In addition, autophagy, stem cell maintenance or the newly described intermediate quiescence state, Galert, imply upstream monitoring by the mTOR pathway. In this review, we report the role of mTOR signaling in reparative regenerations in different tissues and body parts (e.g., axon, skeletal muscle, liver, epithelia, appendages, kidney, and whole-body), and highlight how the mTOR kinase can be viewed as a therapeutic target to boost organ repair. Studies in this area have focused on modulating the mTOR pathway in various animal models to elucidate its contribution to regeneration. The diversity of metazoan species used to identify the implication of this pathway might then serve applied medicine (in better understanding what is required for efficient treatments in human diseases) but also evolutionary biology. Indeed, species-specific differences in mTOR modulation can contain the keys to appreciate why certain regeneration processes have been lost or conserved in the animal kingdom.

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Targeting mammalian target of rapamycin: prospects for the treatment of inflammatory bowel diseases

Current Medicinal Chemistry ◽

10.2174/0929867327666200504081503 ◽

2020 ◽

Vol 27 ◽

Author(s):

Naser-Aldin Lashgari ◽

Nazanin Momeni Roudsari ◽

Saeideh Momtaz ◽

Negar Ghanaatian ◽

Parichehr Kohansal ◽

...

Keyword(s):

Signaling Pathway ◽

Mammalian Target Of Rapamycin ◽

Mtor Pathway ◽

Mtor Signaling ◽

Target Of Rapamycin ◽

In Vivo Studies ◽

Cochrane Library ◽

Mtor Signaling Pathway ◽

Inflammatory Bowel

: Inflammatory bowel disease (IBD) is a general term for a group of chronic and progressive disorders. Several cellular and biomolecular pathways are implicated in the pathogenesis of IBD, yet the etiology is unclear. Activation of the mammalian target of rapamycin (mTOR) pathway in the intestinal epithelial cells was also shown to induce inflammation. This review focuses on the inhibition of the mTOR signaling pathway and its potential application in treating IBD. We also provide an overview on plant-derived compounds that are beneficial for the IBD management through modulation of the mTOR pathway. Data were extracted from clinical, in vitro and in vivo studies published in English between 1995 and May 2019, which were collected from PubMed, Google Scholar, Scopus and Cochrane library databases. Results of various studies implied that inhibition of the mTOR signaling pathway downregulates the inflammatory processes and cytokines involved in IBD. In this context, a number of natural products might reverse the pathological features of the disease. Furthermore, mTOR provides a novel drug target for IBD. Comprehensive clinical studies are required to confirm the efficacy of mTOR inhibitors in treating IBD.

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Targeting AKT/mTOR in Oral Cancer: Mechanisms and Advances in Clinical Trials

International Journal of Molecular Sciences ◽

10.3390/ijms21093285 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3285 ◽

Cited By ~ 5

Author(s):

Choudhary Harsha ◽

Kishore Banik ◽

Hui Li Ang ◽

Sosmitha Girisa ◽

Rajesh Vikkurthi ◽

...

Keyword(s):

Oral Cancer ◽

Epithelial To Mesenchymal Transition ◽

Mammalian Target Of Rapamycin ◽

Mtor Inhibitors ◽

Mtor Pathway ◽

Mtor Signaling ◽

Therapeutic Interventions ◽

Treatment Modalities ◽

Disease Heterogeneity ◽

Mesenchymal Transition

Oral cancer (OC) is a devastating disease that takes the lives of lots of people globally every year. The current spectrum of treatment modalities does not meet the needs of the patients. The disease heterogeneity demands personalized medicine or targeted therapies. Therefore, there is an urgent need to identify potential targets for the treatment of OC. Abundant evidence has suggested that the components of the protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway are intrinsic factors for carcinogenesis. The AKT protein is central to the proliferation and survival of normal and cancer cells, and its downstream protein, mTOR, also plays an indispensable role in the cellular processes. The wide involvement of the AKT/mTOR pathway has been noted in oral squamous cell carcinoma (OSCC). This axis significantly regulates the various hallmarks of cancer, like proliferation, survival, angiogenesis, invasion, metastasis, autophagy, and epithelial-to-mesenchymal transition (EMT). Activated AKT/mTOR signaling is also associated with circadian signaling, chemoresistance and radio-resistance in OC cells. Several miRNAs, circRNAs and lncRNAs also modulate this pathway. The association of this axis with the process of tumorigenesis has culminated in the identification of its specific inhibitors for the prevention and treatment of OC. In this review, we discussed the significance of AKT/mTOR signaling in OC and its potential as a therapeutic target for the management of OC. This article also provided an update on several AKT/mTOR inhibitors that emerged as promising candidates for therapeutic interventions against OC/head and neck cancer (HNC) in clinical studies.

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An Emerging Role for IQGAP1 in Regulating Protein Traffic

The Scientific World JOURNAL ◽

10.1100/tsw.2010.85 ◽

2010 ◽

Vol 10 ◽

pp. 944-953 ◽

Cited By ~ 19

Author(s):

Mahasin Osman

Keyword(s):

Cell Growth ◽

Specific Inhibitor ◽

Membrane Traffic ◽

Mtor Pathway ◽

Human Diseases ◽

Multifunctional Protein ◽

Intracellular Traffic ◽

Human Cancers ◽

C Terminus ◽

Wide Range

IQGAP1, an effector of CDC42p GTPase, is a widely conserved, multifunctional protein that bundles F-actin through its N-terminus and binds microtubules through its C-terminus to modulate the cell architecture. It has emerged as a potential oncogene associated with diverse human cancers. Therefore, IQGAP1 has been heavily investigated; regardless, its precise cellular function remains unclear. Work from yeast suggests that IQGAP1 plays an important role in directed cell growth, which is a conserved feature crucial to morphogenesis, division axis, and body plan determination. New evidence suggests a conserved role for IQGAP1 in protein synthesis and membrane traffic, which may help to explain the diversity of its cellular functions. Membrane traffic mediates infections by intracellular pathogens and a range of degenerative human diseases arise from dysfunctions in intracellular traffic; thus, elucidating the mechanisms of cellular traffic will be important in order to understand the basis of a wide range of inherited and acquired human diseases. Recent evidence suggests that IQGAP1 plays its role in cell growth through regulating the conserved mTOR pathway. The mTOR signaling cascade has been implicated in membrane traffic and is activated in nearly all human cancers, but clinical response to the mTOR-specific inhibitor rapamycin has been disappointing. Thus, understanding the regulators of this pathway will be crucial in order to identify predictors of rapamycin sensitivity. In this review, I discuss emerging evidence that supports a potential role of IQGAP1 in regulating membrane traffic via regulating the mTOR pathway.

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Role of mTOR Signaling in Tumor Microenvironment: An Overview

International Journal of Molecular Sciences ◽

10.3390/ijms19082453 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2453 ◽

Cited By ~ 46

Author(s):

Fabiana Conciatori ◽

Chiara Bazzichetto ◽

Italia Falcone ◽

Sara Pilotto ◽

Emilio Bria ◽

...

Keyword(s):

Tumor Microenvironment ◽

Mammalian Target Of Rapamycin ◽

Mtor Pathway ◽

Mtor Signaling ◽

New Combination ◽

Combination Therapies ◽

Cellular Processes ◽

Promising Target ◽

Exogenous Cues

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.

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Beneficial Effects of Resveratrol-Mediated Inhibition of the mTOR Pathway in Spinal Cord Injury

Neural Plasticity ◽

10.1155/2018/7513748 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 5

Author(s):

Jingying Zhou ◽

Xue Huo ◽

Benson O. A. Botchway ◽

Luyao Xu ◽

Xiaofang Meng ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Signaling Pathway ◽

Mammalian Target Of Rapamycin ◽

Mtor Pathway ◽

Mtor Signaling ◽

High Rate ◽

Mtor Signaling Pathway ◽

Beneficial Effects ◽

Cord Injury

Spinal cord injury (SCI) causes a high rate of morbidity and disability. The clinical features of SCI are divided into acute, subacute, and chronic phases according to its pathophysiological events. The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in cell death and inflammation in the acute phase and neuroregeneration in the subacute/chronic phases at different times. Resveratrol has the potential of regulating cell growth, proliferation, metabolism, and angiogenesis through the mTOR signaling pathway. Herein, we explicate the role of resveratrol in the repair of SCI through the inhibition of the mTOR signaling pathway. The inhibition of the mTOR pathway by resveratrol has the potential of serving as a neuronal restorative mechanism following SCI.

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Recent Updates on the Involvement of PI3K/AKT/mTOR Molecular Cascade in the Pathogenesis of Hyperproliferative Skin Disorders

Frontiers in Medicine ◽

10.3389/fmed.2021.665647 ◽

2021 ◽

Vol 8 ◽

Author(s):

Laura Mercurio ◽

Cristina Albanesi ◽

Stefania Madonna

Keyword(s):

Cell Carcinoma ◽

Mammalian Cells ◽

Mammalian Target Of Rapamycin ◽

Mtor Pathway ◽

Mtor Signaling ◽

Keratinocyte Differentiation ◽

Current Status ◽

Regulatory Subunit ◽

Skin Disorders ◽

Phosphoinositide 3 Kinase

PhosphoInositide-3 Kinase (PI3K) represents a family of different classes of kinases which control multiple biological processes in mammalian cells, such as cell growth, proliferation, and survival. Class IA PI3Ks, the main regulators of proliferative signals, consists of a catalytic subunit (α, β, δ) that binds p85 regulatory subunit and mediates activation of AKT and mammalian Target Of Rapamycin (mTOR) pathways and regulation of downstream effectors. Dysregulation of PI3K/AKT/mTOR pathway in skin contributes to several pathological conditions characterized by uncontrolled proliferation, including skin cancers, psoriasis, and atopic dermatitis (AD). Among cutaneous cancers, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) display PI3K/AKT/mTOR signaling hyperactivation, implicated in hyperproliferation, and tumorigenesis, as well as in resistance to apoptosis. Upregulation of mTOR signaling proteins has also been reported in psoriasis, in association with enhanced proliferation, defective keratinocyte differentiation, senescence-like growth arrest, and resistance to apoptosis, accounting for major parts of the overall disease phenotypes. On the contrary, PI3K/AKT/mTOR role in AD is less characterized, even though recent evidence demonstrates the relevant function for mTOR pathway in the regulation of epidermal barrier formation and stratification. In this review, we provide the most recent updates on the role and function of PI3K/AKT/mTOR molecular axis in the pathogenesis of different hyperproliferative skin disorders, and highlights on the current status of preclinical and clinical studies on PI3K-targeted therapies.

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Mammalian Target of Rapamycin Is Activated in Association with Myometrial Proliferation during Pregnancy

Endocrinology ◽

10.1210/en.2009-0419 ◽

2009 ◽

Vol 150 (10) ◽

pp. 4672-4680 ◽

Cited By ~ 41

Author(s):

Shabana Jaffer ◽

Oksana Shynlova ◽

Stephen Lye

Keyword(s):

Insulin Receptor ◽

Signaling Pathway ◽

Mammalian Target Of Rapamycin ◽

Mtor Pathway ◽

Mtor Signaling ◽

Target Of Rapamycin ◽

Insulin Receptor Substrate ◽

Mtor Signaling Pathway ◽

Insulin Receptor Substrate 1 ◽

Ovx Rats

Abstract The adaptive growth of the uterus during gestation involves gradual changes in cellular phenotypes from the early proliferative to the intermediate synthetic phase of cellular hypertrophy, ending in the final contractile/labour phenotype. The mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth and proliferation in many tissues. We hypothesized that mTOR was a mediator of hormone-initiated myometrial hyperplasia during gestation. The protein expression and phosphorylation levels of mTOR, its upstream regulators [insulin receptor substrate-1, phosphoinositide-3-kinase (PI3K), Akt], and downstream effectors [S6-kinase-1 (S6K1) and eI4FE-binding protein 1 (4EBP1)] were analyzed throughout normal pregnancy in rats. In addition, we used an ovariectomized (OVX) rat model to analyze the modulation of the mTOR pathway and proliferative activity of the uterine myocytes by estradiol alone and in combination with the mTOR-specific inhibitor rapamycin. Our results demonstrate that insulin receptor substrate-1 protein levels and the phosphorylated (activated) forms of PI3K, mTOR, and S6K1 were significantly up-regulated in the rat myometrium during the proliferative phase of pregnancy. Treatment of the OVX rats with estradiol caused a transient increase in IGF-I followed by an up-regulation of the PI3K/mTOR pathway, which became apparent by a cascade of phosphorylation reactions (P-P85, P-Akt, P-mTOR, P-S6K1, and P-4EBP1). Rapamycin blocked activation of P-mTOR, P-S6K1, and P-4EBP1 proteins and significantly reduced the number of proliferating cells in the myometrium of OVX rats. Our in vivo data demonstrate that estradiol was able to activate the PI3K/mTOR signaling pathway in uterine myocytes and suggest that this activation is responsible for the induction of myometrial hyperplasia during early gestation.

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The Esophageal Cancer and the PI3K/AKT/mTOR Signaling Regulatory microRNAs: a Novel Marker for Prognosis, and a Possible Target for Immunotherapy

Current Pharmaceutical Design ◽

10.2174/1381612825666190110143258 ◽

2019 ◽

Vol 24 (39) ◽

pp. 4646-4651 ◽

Cited By ~ 5

Author(s):

Seyed A. Javadinia ◽

Soodabeh Shahidsales ◽

Azar Fanipakdel ◽

Asma Mostafapour ◽

Mona Joudi-Mashhad ◽

...

Keyword(s):

Esophageal Cancer ◽

Cross Talk ◽

Therapeutic Target ◽

Cell Biology ◽

Current Knowledge ◽

Mammalian Target Of Rapamycin ◽

Mtor Pathway ◽

Mtor Signaling ◽

Phosphatidylinositol 3 Kinase ◽

Potential Therapeutic Target

The Phosphatidylinositol 3-kinase/AKT/Mammalian Target of Rapamycin (PI3K/AKT/mTOR) pathway has a critical regulatory role in cell biology including translation, transcription, and autophagy. Dysregulation of this pathway is involved in the pathogenesis, development, and prognosis of esophageal cancer that has been assessed in the recent years and its potential as a target in therapy. This report summarizes the current knowledge about PI3K/AKT/mTOR pathway and its cross-talk with a focus on the value of targeting this pathway as a potential therapeutic target in the treatment of esophageal cancer.

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The Roles of Post-Translational Modifications on mTOR Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms22041784 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1784

Author(s):

Shasha Yin ◽

Liu Liu ◽

Wenjian Gan

Keyword(s):

Metabolic Diseases ◽

Lipid Synthesis ◽

Genetic Alterations ◽

Mtor Pathway ◽

Mtor Signaling ◽

Human Diseases ◽

Post Translational Modifications ◽

Downstream Signaling ◽

Cellular Processes ◽

Almost All

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.

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Bnip3 Mediates the Hypoxia-induced Inhibition on Mammalian Target of Rapamycin by Interacting with Rheb

Journal of Biological Chemistry ◽

10.1074/jbc.m705231200 ◽

2007 ◽

Vol 282 (49) ◽

pp. 35803-35813 ◽

Cited By ~ 167

Author(s):

Yong Li ◽

Yian Wang ◽

Eunjung Kim ◽

Peter Beemiller ◽

Cun-Yu Wang ◽

...

Keyword(s):

Cell Growth ◽

Energy Levels ◽

Mammalian Target Of Rapamycin ◽

Small Gtpase ◽

Mtor Pathway ◽

Target Of Rapamycin ◽

Intracellular Signals ◽

Central Controller ◽

Wide Range

The mammalian target of rapamycin (mTOR) is a central controller of cell growth, and it regulates translation, cell size, cell viability, and cell morphology. mTOR integrates a wide range of extracellular and intracellular signals, including growth factors, nutrients, energy levels, and stress conditions. Rheb, a Ras-related small GTPase, is a key upstream activator of mTOR. In this study, we found that Bnip3, a hypoxia-inducible Bcl-2 homology 3 domain-containing protein, directly binds Rheb and inhibits the mTOR pathway. Bnip3 decreases Rheb GTP levels in a manner depending on the binding to Rheb and the presence of the N-terminal domain. Both knockdown and overexpression experiments show that Bnip3 plays an important role in mTOR inactivation in response to hypoxia. Moreover, Bnip3 inhibits cell growth in vivo by suppressing the mTOR pathway. These observations demonstrate that Bnip3 mediates the inhibition of the mTOR pathway in response to hypoxia.

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