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mTOR Signaling: New Insights into Cancer, Cardiovascular Diseases, Diabetes and Aging

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 34699

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Special Issue Editors

Dr. Anindita Das

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Guest Editor

Department of Internal Medicine, Virginia Commonwealth University, 1101 East Marshall Street, Sanger Hall, Rm # 7020B, Richmond, VA 23298, USA
Interests: cardioprotection against myocardial ischemia/reperfusion injury with pharmacological agents, including mTOR inhibitor and phosphodiesterase-5 inhibitor; myocardial pre- and post-conditioning; cardioprotective mechanism in diabetic heart; myocardial infarction; cardiac hypertrophy; heart failure; developing a novel pharmacotherapy against doxorubicin-induced or other anti-cancer drug-induced cardiotoxicity; role of nitric oxide, protein kinase G, mTOR signaling, STAT3 signaling, specific long-non-coding RNA, and microRNA in cardioprotection; inflammation; necrosis; apoptosis; autophagy
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Flávio Reis

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1. Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
2. Institute of Pharmacology & Experimental Therapeutics & Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
Interests: gut microbiota; therapeutics & nutraceuticals; cardiovascular & metabolic disorders; renal diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

The mechanistic target of rapamycin (mTOR), an atypical multidomain serine/threonine kinase of the phosphoinositide 3-kinase (PI3K) related kinase family, elicits a significant role in integrating intracellular and environmental cues that orchestrate gene transcription, protein synthesis, tissue regeneration and repair, oxidative stress, cell metabolism, growth, proliferation, autophagy, apoptosis, survival, and longevity. Aberrant activation of mTOR is potentially associated with the etiology of many pathological conditions, including cancer, obesity and diabetes, cardiovascular diseases, pulmonary hypertension, and neurodegeneration. Based on its pathophysiological importance, the mTOR signaling pathway has attracted unprecedented attention among basic scientists and clinicians. mTOR is the core component of differently composed signaling complexes, mTORC1 and mTORC2, which phosphorylate distinct specific substrates. It is essential to extensively investigate the differential roles of mTORC1 and mTORC2 signaling pathways in human diseases, which could be targeted selectively or in combination, to develop potential therapeutic or nutraceutical interventions to prevent or treat severe diseases and extend life span.

The editors of this Special Issue welcome original research articles, reviews, meta-analyses/systematic reviews, or shorter perspective articles as well as novel technological approaches with an emphasis on the molecular aspects of mTOR signaling in metabolic syndrome, cardiovascular diseases, cancer, and aging, which would advance our knowledge to develop novel therapeutic or nutraceutical strategies to treat many human diseases.

We look forward to your contributions to this Special Issue.

Dr. Flávio Reis
Dr. Anindita Das
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Aging
Apoptosis and autophagy
Cancer
Cardiovascular diseases
Diabetes and other metabolic diseases
Gene targets and therapeutics
Growth and proliferation
Inflammation
Kinases
mTOR signaling
Nutraceuticals

Published Papers (11 papers)

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Editorial

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5 pages, 228 KiB

Open AccessEditorial

mTOR Signaling: New Insights into Cancer, Cardiovascular Diseases, Diabetes and Aging

by Anindita Das and Flávio Reis

Int. J. Mol. Sci. 2023, 24(17), 13628; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241713628 - 04 Sep 2023

Cited by 1 | Viewed by 1213

Abstract

The mechanistic/mammalian target of rapamycin (mTOR), a member of the phosphoinositide 3-kinase (PI3K) related kinase family, integrates intracellular and environmental cues that coordinate a diverse set of cellular/tissue functions, such as cell growth, proliferation, metabolism, autophagy, apoptosis, longevity, protein/lipid/nucleotide synthesis, and tissue regeneration [...] Read more.

(This article belongs to the Special Issue mTOR Signaling: New Insights into Cancer, Cardiovascular Diseases, Diabetes and Aging)

Research

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17 pages, 7394 KiB

Open AccessArticle

Single-Dose Treatment with Rapamycin Preserves Post-Ischemic Cardiac Function through Attenuation of Fibrosis and Inflammation in Diabetic Rabbit

by Arun Samidurai, Manu Saravanan, Ramzi Ockaili, Donatas Kraskauskas, Suet Ying Valerie Lau, Varun Kodali, Shakthi Ramasamy, Karthikeya Bhoopathi, Megha Nair, Sean K. Roh, Rakesh C. Kukreja and Anindita Das

Int. J. Mol. Sci. 2023, 24(10), 8998; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24108998 - 19 May 2023

Cited by 4 | Viewed by 1641

Abstract

Robust activation of mTOR (mammalian target of rapamycin) signaling in diabetes exacerbates myocardial injury following lethal ischemia due to accelerated cardiomyocyte death with cardiac remodeling and inflammatory responses. We examined the effect of rapamycin (RAPA, mTOR inhibitor) on cardiac remodeling and inflammation following myocardial ischemia/reperfusion (I/R) injury in diabetic rabbits. Diabetic rabbits (DM) were subjected to 45 min of ischemia and 10 days of reperfusion by inflating/deflating a previously implanted hydraulic balloon occluder. RAPA (0.25 mg/kg, i.v.) or DMSO (vehicle) was infused 5 min before the onset of reperfusion. Post-I/R left ventricular (LV) function was assessed by echocardiography and fibrosis was evaluated by picrosirius red staining. Treatment with RAPA preserved LV ejection fraction and reduced fibrosis. Immunoblot and real-time PCR revealed that RAPA treatment inhibited several fibrosis markers (TGF-β, Galectin-3, MYH, p-SMAD). Furthermore, immunofluorescence staining revealed the attenuation of post-I/R NLRP3-inflammasome formation with RAPA treatment as shown by reduced aggregation of apoptosis speck-like protein with a caspase recruitment domain and active-form of caspase-1 in cardiomyocytes. In conclusion, our study suggests that acute reperfusion therapy with RAPA may be a viable strategy to preserve cardiac function with the alleviation of adverse post-infarct myocardial remodeling and inflammation in diabetic patients. Full article

(This article belongs to the Special Issue mTOR Signaling: New Insights into Cancer, Cardiovascular Diseases, Diabetes and Aging)

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12 pages, 3138 KiB

Open AccessCommunication

AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans

by Tinka Vidovic, Alexander Dakhovnik, Oleksii Hrabovskyi, Michael R. MacArthur and Collin Y. Ewald

Int. J. Mol. Sci. 2023, 24(9), 7850; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24097850 - 25 Apr 2023

Cited by 1 | Viewed by 3999

Abstract

The mechanistic target of rapamycin (mTOR) kinase is one of the top drug targets for promoting health and lifespan extension. Besides rapamycin, only a few other mTOR inhibitors have been developed and shown to be capable of slowing aging. We used machine learning to predict novel small molecules targeting mTOR. We selected one small molecule, TKA001, based on in silico predictions of a high on-target probability, low toxicity, favorable physicochemical properties, and preferable ADMET profile. We modeled TKA001 binding in silico by molecular docking and molecular dynamics. TKA001 potently inhibits both TOR complex 1 and 2 signaling in vitro. Furthermore, TKA001 inhibits human cancer cell proliferation in vitro and extends the lifespan of Caenorhabditis elegans, suggesting that TKA001 is able to slow aging in vivo. Full article

(This article belongs to the Special Issue mTOR Signaling: New Insights into Cancer, Cardiovascular Diseases, Diabetes and Aging)

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16 pages, 1949 KiB

Open AccessArticle

High Glucose-Induced Cardiomyocyte Damage Involves Interplay between Endothelin ET-1/ET_A/ET_B Receptor and mTOR Pathway

by Sudhir Pandey, Corina T. Madreiter-Sokolowski, Supachoke Mangmool and Warisara Parichatikanond

Int. J. Mol. Sci. 2022, 23(22), 13816; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232213816 - 10 Nov 2022

Cited by 4 | Viewed by 1911

Abstract

Patients with type two diabetes mellitus (T2DM) are at increased risk for cardiovascular diseases. Impairments of endothelin-1 (ET-1) signaling and mTOR pathway have been implicated in diabetic cardiomyopathies. However, the molecular interplay between the ET-1 and mTOR pathway under high glucose (HG) conditions in H9c2 cardiomyoblasts has not been investigated. We employed MTT assay, qPCR, western blotting, fluorescence assays, and confocal microscopy to assess the oxidative stress and mitochondrial damage under hyperglycemic conditions in H9c2 cells. Our results showed that HG-induced cellular stress leads to a significant decline in cell survival and an impairment in the activation of ET_A-R/ET_B-R and the mTOR main components, Raptor and Rictor. These changes induced by HG were accompanied by a reactive oxygen species (ROS) level increase and mitochondrial membrane potential (MMP) loss. In addition, the fragmentation of mitochondria and a decrease in mitochondrial size were observed. However, the inhibition of either ET_A-R alone by ambrisentan or ET_A-R/ET_B-R by bosentan or the partial blockage of the mTOR function by silencing Raptor or Rictor counteracted those adverse effects on the cellular function. Altogether, our findings prove that ET-1 signaling under HG conditions leads to a significant mitochondrial dysfunction involving contributions from the mTOR pathway. Full article

(This article belongs to the Special Issue mTOR Signaling: New Insights into Cancer, Cardiovascular Diseases, Diabetes and Aging)

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17 pages, 2066 KiB

Open AccessArticle

GSK3β Serine 389 Phosphorylation Modulates Cardiomyocyte Hypertrophy and Ischemic Injury

by Laura Vainio, Saija Taponen, Sini M. Kinnunen, Eveliina Halmetoja, Zoltan Szabo, Tarja Alakoski, Johanna Ulvila, Juhani Junttila, Päivi Lakkisto, Johanna Magga and Risto Kerkelä

Int. J. Mol. Sci. 2021, 22(24), 13586; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413586 - 18 Dec 2021

Cited by 4 | Viewed by 2434

Abstract

Prior studies show that glycogen synthase kinase 3β (GSK3β) contributes to cardiac ischemic injury and cardiac hypertrophy. GSK3β is constitutionally active and phosphorylation of GSK3β at serine 9 (S9) inactivates the kinase and promotes cellular growth. GSK3β is also phosphorylated at serine 389 (S389), but the significance of this phosphorylation in the heart is not known. We analyzed GSK3β S389 phosphorylation in diseased hearts and utilized overexpression of GSK3β carrying ser→ala mutations at S9 (S9A) and S389 (S389A) to study the biological function of constitutively active GSK3β in primary cardiomyocytes. We found that phosphorylation of GSK3β at S389 was increased in left ventricular samples from patients with dilated cardiomyopathy and ischemic cardiomyopathy, and in hearts of mice subjected to thoracic aortic constriction. Overexpression of either GSK3β S9A or S389A reduced the viability of cardiomyocytes subjected to hypoxia–reoxygenation. Overexpression of double GSK3β mutant (S9A/S389A) further reduced cardiomyocyte viability. Determination of protein synthesis showed that overexpression of GSK3β S389A or GSK3β S9A/S389A increased both basal and agonist-induced cardiomyocyte growth. Mechanistically, GSK3β S389A mutation was associated with activation of mTOR complex 1 signaling. In conclusion, our data suggest that phosphorylation of GSK3β at S389 enhances cardiomyocyte survival and protects from cardiomyocyte hypertrophy. Full article

(This article belongs to the Special Issue mTOR Signaling: New Insights into Cancer, Cardiovascular Diseases, Diabetes and Aging)

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14 pages, 4962 KiB

Open AccessArticle

Biodegradable Stent with mTOR Inhibitor-Eluting Reduces Progression of Ureteral Stricture

by Dong-Ru Ho, Shih-Horng Su, Pey-Jium Chang, Wei-Yu Lin, Yun-Ching Huang, Jian-Hui Lin, Kuo-Tsai Huang, Wai-Nga Chan and Chih-Shou Chen

Int. J. Mol. Sci. 2021, 22(11), 5664; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115664 - 26 May 2021

Cited by 11 | Viewed by 2826

Abstract

In this study, we investigated the effect of mTOR inhibitor (mTORi) drug-eluting biodegradable stent (DE stent), a putative restenosis-inhibiting device for coronary artery, on thermal-injury-related ureteral stricture in rabbits. In vitro evaluation confirmed the dose-dependent effect of mTORi, i.e., rapamycin, on fibrotic markers in ureteral component cell lines. Upper ureteral fibrosis was induced by ureteral thermal injury in open surgery, which was followed by insertion of biodegradable stents, with or without rapamycin drug-eluting. Immunohistochemistry and Western blotting were performed 4 weeks after the operation to determine gross anatomy changes, collagen deposition, expression of epithelial–mesenchymal transition markers, including Smad, α-SMA, and SNAI 1. Ureteral thermal injury resulted in severe ipsilateral hydronephrosis. The levels of type III collagen, Smad, α-SMA, and SNAI 1 were increased 28 days after ureteral thermal injury. Treatment with mTORi-eluting biodegradable stents significantly attenuated thermal injury-induced urinary tract obstruction and reduced the level of fibrosis proteins, i.e., type III collagen. TGF-β and EMT signaling pathway markers, Smad and SNAI 1, were significantly modified in DE stent-treated thermal-injury-related ureteral stricture rabbits. These results suggested that intra-ureteral administration of rapamycin by DE stent provides modification of fibrosis signaling pathway, and inhibiting mTOR may result in fibrotic process change. Full article

(This article belongs to the Special Issue mTOR Signaling: New Insights into Cancer, Cardiovascular Diseases, Diabetes and Aging)

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Review

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29 pages, 2168 KiB

Open AccessReview

Unveiling Novel Avenues in mTOR-Targeted Therapeutics: Advancements in Glioblastoma Treatment

by Shilpi Singh, Debashis Barik, Karl Lawrie, Iteeshree Mohapatra, Sujata Prasad, Afsar R. Naqvi, Amar Singh and Gatikrushna Singh

Int. J. Mol. Sci. 2023, 24(19), 14960; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241914960 - 06 Oct 2023

Cited by 2 | Viewed by 1482

Abstract

The mTOR signaling pathway plays a pivotal and intricate role in the pathogenesis of glioblastoma, driving tumorigenesis and proliferation. Mutations or deletions in the PTEN gene constitutively activate the mTOR pathway by expressing growth factors EGF and PDGF, which activate their respective receptor pathways (e.g., EGFR and PDGFR). The convergence of signaling pathways, such as the PI3K-AKT pathway, intensifies the effect of mTOR activity. The inhibition of mTOR has the potential to disrupt diverse oncogenic processes and improve patient outcomes. However, the complexity of the mTOR signaling, off-target effects, cytotoxicity, suboptimal pharmacokinetics, and drug resistance of the mTOR inhibitors pose ongoing challenges in effectively targeting glioblastoma. Identifying innovative treatment strategies to address these challenges is vital for advancing the field of glioblastoma therapeutics. This review discusses the potential targets of mTOR signaling and the strategies of target-specific mTOR inhibitor development, optimized drug delivery system, and the implementation of personalized treatment approaches to mitigate the complications of mTOR inhibitors. The exploration of precise mTOR-targeted therapies ultimately offers elevated therapeutic outcomes and the development of more effective strategies to combat the deadliest form of adult brain cancer and transform the landscape of glioblastoma therapy. Full article

(This article belongs to the Special Issue mTOR Signaling: New Insights into Cancer, Cardiovascular Diseases, Diabetes and Aging)

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23 pages, 739 KiB

Open AccessReview

Regulation of mTOR Signaling: Emerging Role of Cyclic Nucleotide-Dependent Protein Kinases and Implications for Cardiometabolic Disease

by Fubiao Shi and Sheila Collins

Int. J. Mol. Sci. 2023, 24(14), 11497; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241411497 - 15 Jul 2023

Cited by 4 | Viewed by 2145

Abstract

The mechanistic target of rapamycin (mTOR) kinase is a central regulator of cell growth and metabolism. It is the catalytic subunit of two distinct large protein complexes, mTOR complex 1 (mTORC1) and mTORC2. mTOR activity is subjected to tight regulation in response to external nutrition and growth factor stimulation. As an important mechanism of signaling transduction, the ‘second messenger’ cyclic nucleotides including cAMP and cGMP and their associated cyclic nucleotide-dependent kinases, including protein kinase A (PKA) and protein kinase G (PKG), play essential roles in mediating the intracellular action of a variety of hormones and neurotransmitters. They have also emerged as important regulators of mTOR signaling in various physiological and disease conditions. However, the mechanism by which cAMP and cGMP regulate mTOR activity is not completely understood. In this review, we will summarize the earlier work establishing the ability of cAMP to dampen mTORC1 activation in response to insulin and growth factors and then discuss our recent findings demonstrating the regulation of mTOR signaling by the PKA- and PKG-dependent signaling pathways. This signaling framework represents a new non-canonical regulation of mTOR activity that is independent of AKT and could be a novel mechanism underpinning the action of a variety of G protein-coupled receptors that are linked to the mTOR signaling network. We will further review the implications of these signaling events in the context of cardiometabolic disease, such as obesity, non-alcoholic fatty liver disease, and cardiac remodeling. The metabolic and cardiac phenotypes of mouse models with targeted deletion of Raptor and Rictor, the two essential components for mTORC1 and mTORC2, will be summarized and discussed. Full article

(This article belongs to the Special Issue mTOR Signaling: New Insights into Cancer, Cardiovascular Diseases, Diabetes and Aging)

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18 pages, 1782 KiB

Open AccessReview

The Importance of mTORC1-Autophagy Axis for Skeletal Muscle Diseases

by Xujun Han, Kah Yong Goh, Wen Xing Lee, Sze Mun Choy and Hong-Wen Tang

Int. J. Mol. Sci. 2023, 24(1), 297; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010297 - 24 Dec 2022

Cited by 9 | Viewed by 3577

Abstract

The mechanistic target of rapamycin (mTOR) complex 1, mTORC1, integrates nutrient and growth factor signals with cellular responses and plays critical roles in regulating cell growth, proliferation, and lifespan. mTORC1 signaling has been reported as a central regulator of autophagy by modulating almost all aspects of the autophagic process, including initiation, expansion, and termination. An increasing number of studies suggest that mTORC1 and autophagy are critical for the physiological function of skeletal muscle and are involved in diverse muscle diseases. Here, we review recent insights into the essential roles of mTORC1 and autophagy in skeletal muscles and their implications in human muscle diseases. Multiple inhibitors targeting mTORC1 or autophagy have already been clinically approved, while others are under development. These chemical modulators that target the mTORC1/autophagy pathways represent promising potentials to cure muscle diseases. Full article

(This article belongs to the Special Issue mTOR Signaling: New Insights into Cancer, Cardiovascular Diseases, Diabetes and Aging)

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20 pages, 3313 KiB

Open AccessReview

Feedback, Crosstalk and Competition: Ingredients for Emergent Non-Linear Behaviour in the PI3K/mTOR Signalling Network

by Milad Ghomlaghi, Anthony Hart, Nhan Hoang, Sungyoung Shin and Lan K. Nguyen

Int. J. Mol. Sci. 2021, 22(13), 6944; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136944 - 28 Jun 2021

Cited by 15 | Viewed by 4569

Abstract

The PI3K/mTOR signalling pathway plays a central role in the governing of cell growth, survival and metabolism. As such, it must integrate and decode information from both external and internal sources to guide efficient decision-making by the cell. To facilitate this, the pathway has evolved an intricate web of complex regulatory mechanisms and elaborate crosstalk with neighbouring signalling pathways, making it a highly non-linear system. Here, we describe the mechanistic biological details that underpin these regulatory mechanisms, covering a multitude of negative and positive feedback loops, feed-forward loops, competing protein interactions, and crosstalk with major signalling pathways. Further, we highlight the non-linear and dynamic network behaviours that arise from these regulations, uncovered through computational and experimental studies. Given the pivotal role of the PI3K/mTOR network in cellular homeostasis and its frequent dysregulation in pathologies including cancer and diabetes, a coherent and systems-level understanding of the complex regulation and consequential dynamic signalling behaviours within this network is imperative for advancing biology and development of new therapeutic approaches. Full article

(This article belongs to the Special Issue mTOR Signaling: New Insights into Cancer, Cardiovascular Diseases, Diabetes and Aging)

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19 pages, 1876 KiB

Open AccessReview

mTOR Signaling in the Inner Ear as Potential Target to Treat Hearing Loss

by Maurizio Cortada, Soledad Levano and Daniel Bodmer

Int. J. Mol. Sci. 2021, 22(12), 6368; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126368 - 14 Jun 2021

Cited by 10 | Viewed by 7191

Abstract

Hearing loss affects many people worldwide and occurs often as a result of age, ototoxic drugs and/or excessive noise exposure. With a growing number of elderly people, the number of people suffering from hearing loss will also increase in the future. Despite the high number of affected people, for most patients there is no curative therapy for hearing loss and hearing aids or cochlea implants remain the only option. Important treatment approaches for hearing loss include the development of regenerative therapies or the inhibition of cell death/promotion of cell survival pathways. The mammalian target of rapamycin (mTOR) pathway is a central regulator of cell growth, is involved in cell survival, and has been shown to be implicated in many age-related diseases. In the inner ear, mTOR signaling has also started to gain attention recently. In this review, we will emphasize recent discoveries of mTOR signaling in the inner ear and discuss implications for possible treatments for hearing restoration. Full article

(This article belongs to the Special Issue mTOR Signaling: New Insights into Cancer, Cardiovascular Diseases, Diabetes and Aging)

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