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Special Issue "mTOR in Human Diseases"

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: 10 January 2019

Special Issue Editor

Guest Editor
Dr. Olivier Dormond

Department of Visceral Surgery, Lausanne University Hospital, Pavillon 4, Avenue de Beaumont, 1011 Lausanne, Switzerland
Website | E-Mail
Interests: mTOR; tumor growth; cell signaling; tumor microenvironment

Special Issue Information

Dear Colleagues,

The mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that is ubiquitously expressed. It represents a major signaling intermediary that coordinates favorable environmental conditions with cell growth. Indeed, as part of two functionally distinct protein complexes, named mTORC1 and mTORC2, mTOR regulates a variety of cellular processes including protein, lipid and nucleotide synthesis as well as autophagy. Over the last two decades, major molecular advances have been made in mTOR signaling and have revealed the complexity of the events implicated in mTOR function and regulation. In parallel, the role of mTOR in diverse pathological conditions has also been identified including cancer, hamartoma, neurological and metabolic diseases. Accordingly, therapies that target mTOR benefit patients in various clinical settings. For instance, mTOR inhibitors are used as immunosuppressive drugs, in drug-eluting stents to prevent coronary restenosis following angioplasty or as anti-cancer treatments. It is therefore important to further fully investigate mTOR signaling at a molecular level in order to identify additional clinical opportunities of targeting mTOR in human disorders. This Special Issue of “mTOR in Human Diseases” will cover a selection of research articles related to mTOR in human pathologies. Emphasis will be given to the molecular aspects of mTOR in specific conditions. Experimental studies, review articles and commentaries are all welcome.

Dr. Olivier Dormond
Guest Editor

Manuscript Submission Information

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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 monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). 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

  • mTOR
  • cell signaling
  • growth
  • autophagy
  • cancer
  • hamartoma
  • tuberous sclerosis
  • ageing

Published Papers (16 papers)

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Research

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Open AccessArticle NVP-BEZ235 Attenuated Cell Proliferation and Migration in the Squamous Cell Carcinoma of Oral Cavities and p70S6K Inhibition Mimics its Effect
Int. J. Mol. Sci. 2018, 19(11), 3546; https://doi.org/10.3390/ijms19113546
Received: 9 October 2018 / Revised: 8 November 2018 / Accepted: 8 November 2018 / Published: 10 November 2018
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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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Open AccessArticle Combined Fluid Shear Stress and Melatonin Enhances the ERK/Akt/mTOR Signal in Cilia-Less MC3T3-E1 Preosteoblast Cells
Int. J. Mol. Sci. 2018, 19(10), 2929; https://doi.org/10.3390/ijms19102929
Received: 30 August 2018 / Revised: 22 September 2018 / Accepted: 23 September 2018 / Published: 26 September 2018
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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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Open AccessArticle Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway
Int. J. Mol. Sci. 2018, 19(8), 2183; https://doi.org/10.3390/ijms19082183
Received: 7 June 2018 / Revised: 18 July 2018 / Accepted: 20 July 2018 / Published: 26 July 2018
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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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Open AccessArticle Dopamine Receptor Subtypes Differentially Regulate Autophagy
Int. J. Mol. Sci. 2018, 19(5), 1540; https://doi.org/10.3390/ijms19051540
Received: 4 April 2018 / Revised: 15 May 2018 / Accepted: 18 May 2018 / Published: 22 May 2018
Cited by 2 | PDF Full-text (3604 KB) | HTML Full-text | XML Full-text | Supplementary Files
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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Open AccessArticle mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor Behavior and SLC5A5 mRNA Expression
Int. J. Mol. Sci. 2018, 19(5), 1448; https://doi.org/10.3390/ijms19051448
Received: 2 May 2018 / Revised: 7 May 2018 / Accepted: 7 May 2018 / Published: 13 May 2018
Cited by 1 | PDF Full-text (3132 KB) | HTML Full-text | XML Full-text | Supplementary Files
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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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
Int. J. Mol. Sci. 2018, 19(4), 1250; https://doi.org/10.3390/ijms19041250
Received: 23 March 2018 / Revised: 17 April 2018 / Accepted: 17 April 2018 / Published: 20 April 2018
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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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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
Int. J. Mol. Sci. 2018, 19(2), 382; https://doi.org/10.3390/ijms19020382
Received: 6 December 2017 / Revised: 17 January 2018 / Accepted: 23 January 2018 / Published: 27 January 2018
Cited by 2 | PDF Full-text (1644 KB) | HTML Full-text | XML Full-text | Supplementary Files
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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Open AccessReview mTOR Complexes as a Nutrient Sensor for Driving Cancer Progression
Int. J. Mol. Sci. 2018, 19(10), 3267; https://doi.org/10.3390/ijms19103267
Received: 16 September 2018 / Revised: 14 October 2018 / Accepted: 14 October 2018 / Published: 21 October 2018
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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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Open AccessReview Role of mTOR Signaling in Tumor Microenvironment: An Overview
Int. J. Mol. Sci. 2018, 19(8), 2453; https://doi.org/10.3390/ijms19082453
Received: 11 July 2018 / Revised: 6 August 2018 / Accepted: 15 August 2018 / Published: 19 August 2018
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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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Open AccessReview Biological Aspects of mTOR in Leukemia
Int. J. Mol. Sci. 2018, 19(8), 2396; https://doi.org/10.3390/ijms19082396
Received: 17 July 2018 / Revised: 7 August 2018 / Accepted: 10 August 2018 / Published: 14 August 2018
PDF Full-text (830 KB) | HTML Full-text | XML Full-text
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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Open AccessReview mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases
Int. J. Mol. Sci. 2018, 19(8), 2325; https://doi.org/10.3390/ijms19082325
Received: 4 June 2018 / Revised: 22 July 2018 / Accepted: 30 July 2018 / Published: 8 August 2018
PDF Full-text (711 KB) | HTML Full-text | XML Full-text
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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Open AccessReview mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders
Int. J. Mol. Sci. 2018, 19(8), 2226; https://doi.org/10.3390/ijms19082226
Received: 4 July 2018 / Revised: 26 July 2018 / Accepted: 27 July 2018 / Published: 30 July 2018
Cited by 1 | PDF Full-text (1543 KB) | HTML Full-text | XML Full-text
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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Open AccessReview mTOR and Tumor Cachexia
Int. J. Mol. Sci. 2018, 19(8), 2225; https://doi.org/10.3390/ijms19082225
Received: 3 July 2018 / Revised: 23 July 2018 / Accepted: 25 July 2018 / Published: 30 July 2018
Cited by 1 | PDF Full-text (2121 KB) | HTML Full-text | XML Full-text
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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Open AccessReview Role of mTOR in Glucose and Lipid Metabolism
Int. J. Mol. Sci. 2018, 19(7), 2043; https://doi.org/10.3390/ijms19072043
Received: 31 May 2018 / Revised: 10 July 2018 / Accepted: 11 July 2018 / Published: 13 July 2018
PDF Full-text (491 KB) | HTML Full-text | XML Full-text
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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Open AccessReview Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update
Int. J. Mol. Sci. 2018, 19(7), 1878; https://doi.org/10.3390/ijms19071878
Received: 13 June 2018 / Revised: 22 June 2018 / Accepted: 24 June 2018 / Published: 26 June 2018
Cited by 1 | PDF Full-text (757 KB) | HTML Full-text | XML Full-text
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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Open AccessReview Targeting mTOR as a Therapeutic Approach in Medulloblastoma
Int. J. Mol. Sci. 2018, 19(7), 1838; https://doi.org/10.3390/ijms19071838
Received: 24 May 2018 / Revised: 12 June 2018 / Accepted: 20 June 2018 / Published: 22 June 2018
PDF Full-text (1071 KB) | HTML Full-text | XML Full-text
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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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Preliminary Title: The functions of mTOR signaling in myelinating glia
Author: Bogdan K. Beirowski

Title: Role of mTOR signaling in tumor microenvironment interactions at a glance
Authors: Conciatori Fabiana1,2, Bazzichetto Chiara1,2, Falcone Italia1, Cognetti Francesco 1, Milella Michele 1 and Ciuffreda Ludovica *1
1
Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy
2 University of Rome, La Sapienza, Rome, Italy
(* e-mail: [email protected]; [email protected])
Summary: The mammalian target of rapamycin (mTOR) forms two functionally and structurally distinct multi-component complexes, named mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), and integrates a variety of exogenous cues, including diverse environmental inputs in the immune microenvironment. The mTOR pathway regulates several physiological events, such as differentiation, function and metabolic regulation in innate/adaptive immune cells, as demonstrated by the use of rapamycin in clinical practice as an immune suppressant in organ transplant patients. Moreover, its deregulation is implicated in pathological condition including neoplastic transformation and progression, such as breast, gastrointestinal, liver and prostate cancers.
The mTOR pathway controls the cellular response to pathogens and tumors by regulating macrophages and other innate cells, by modulating the NF-κB and/or STAT activity and the expression of inflammatory factors, such as cytokines/chemokines (i.e. IL-10, TGF-β, and PDL1). By cytokines/chemokines-cytokines/chemokines receptor interactions, tumor microenvironment (TME) recruits immune cells: once activated, immune cells could exercise anti-tumor effects functions or promote cancer cells’ growth. Thus, inflammation plays a central role in tumor dynamic and represents one of the hallmarks of cancer.
Along with the immune system, TME is also characterized by tumor vasculature, in which mTOR pathway regulates cell growth by its effects on cell cycle regulators and nutrient up-take into the cell’s environment, through the promotion of angiogenesis. One of the most prominent effect of mTOR under hypoxia condition is the translation of hypoxia-inducible factor 1 (HIF-1)/HIF-2. The HIF transcription factors lead the expression of hypoxic stress response genes, including angiogenic growth factors such as vascular endothelial growth factor (VEGF), transforming growth factor a (TGF-α) and platelet-derived growth factor β (PDGF-β).
This review highlights the role of mTOR in the interactions between tumor and non-tumor cells in order to better analyze the mechanism of cancer progression and metastasis and drug resistance development.

Title: mTORC inhibitors as broad-spectrum therapeutics for age-related diseases
Authors: Hannah Walters and Lynne S Cox *
Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU
* [email protected]
Abstract: Chronological age represents the greatest risk factor for many life-threatening diseases including neurodegeneration, cancer and cardiovascular disease; ageing also increases an individual’s susceptibility to infectious disease. Current efforts to treat age-related pathologies as individual diseases have had limited success, and development of effective therapies for individual diseases may still not greatly increase the ‘healthspan’ of elderly patients, who will still be vulnerable to the progression of 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 is a regulatory nexus heavily implicated in both ageing and senescence. Excitingly, a growing body of research has revealed that rapamycin and other mTOR inhibitors are promising treatments for a broad spectrum of age-related pathologies, including neurodegeneration, cancer, immunosenescence, osteoporosis, rheumatoid arthritis, age-related blindness, diabetic nephropathy, muscular dystrophy, incontinence and cardiovascular disease. In this review, we assess the evidence supporting use of mTOR inhibitors to treat age-related pathologies, and discuss possible molecular mechanisms of action where evidence is available. We discuss strategies to minimise undesirable side effects of rapamycin and its analogues during treatment of age-related diseases, and emphasize the urgent need for reliable, non-invasive biomarkers of senescence and biological ageing to better monitor the efficacy of any healthy ageing therapy.

Title: mTOR pathway in papillary thyroid carcinoma: different contributions of mTORC1 and mTORC2 complexes for tumor behavior and SLC5A5 mRNA expression
Authors: Paula Soares and Catarina Tavares
Abstract: mTOR pathway is overactivated in thyroid cancer. We previously demonstrated that pmTOR expression is associated with tumor aggressiveness, therapy resistance and lower SLC5A5 mRNA expression in papillary thyroid carcinomas (PTCs), while pS6 (mTORC1 effector) expression was associated with less aggressive clinicopathological features. The distinct behavior of the two markers led us to hypothesized, that mTOR activation could be contributing, in PTC, to a preferential activation of mTORC2 complex.
We performed immunohistochemistry for pAKT Ser473 (mTORC2 effector) in a series of 182 PTCs previously characterized for pmTOR and pS6 expression. We analyzed the impact of each mTOR complex on SLC5A5 mRNA expression, by treating PTC derived cell lines with RAD001 (mTORC1 blocker) and Torin 2 (mTORC1 and mTORC2 blocker).
pAKT Ser473 expression was positively correlated with pmTOR expression. pAKT Ser473 nuclear expression was significantly associated with the presence of distant metastases. Treatment of cell lines with RAD001 had no consequences on SLC5A5 mRNA levels, whereas Torin2 caused a ~6fold increase of SLC5A5 mRNA expression in TPC1 cell line.
mTORC2 activation may be involved in distant metastization and its inhibition upregulates the expression of SLC5A5 mRNA. Pharmacological inhibition of mTORC2 complex should be further addressed in the management of RAI resistant PTC.

Title: Neuronal plasticity mediated by the mTOR pathway as a target for treatment of schizophrenia and mood disorders: focus on AMPA receptor-dependent mechanisms
Authors: Ginetta Collo1, 2, Emiliangelo Ratti3 and Emilio Merlo Pich4
Affiliations: 1Department of Molecular and Translational Medicine, Section of Pharmacology, University of Brescia, 25123 Brescia, Italy; 2Department of Biomedicine, University of Basel, Basel, Switzerland; 3Neuroscience Therapeutic Area Unit, Takeda Pharmaceutical International Co, MA 02139 Cambridge, MA; 4Neuroscience Therapeutic Area Unit, Takeda Pharmaceutical International AG, 8152 Zurich, Switzerland
Abstract: Converging findings point to a critical role of impaired adaptive capacity (neuroplasticity) of different neuronal systems/networks to respond to endogenous and environmental stimuli in determining key symptoms of neuropsychiatric disorders. Among the molecular underpinnings of neuroplasticity, a central role has been recently attributed to the mTOR pathway.  Discovered and initially characterized in peripheral tissues and in cancer cells, the mTOR pathway has been found relevant also in the mammalian nervous system, mediating a series of functional (e.g., LTP, sensitization) and structural (e.g., dendritic outgrowth, synaptic terminal number, soma size) changes in glutamatergic and dopaminergic neurons.  Trophic factors, such as BDNF and insulin-like growth factor, have been listed among the typical activators of the mTOR pathway, whose alterations due to gain- or loss-of-function mutation or systemic up- or down-regulation may affect the adaptive and metabolic capacity of the neurons, resulting in structural hypertrophy (as seen in autism) or hypotrophy (proposed in Mood Disorder), respectively.   In the last few years evidence of connections between the mTOR pathway and the activity of the neurotransmitter glutamate via the engagement of its receptors NMDA and AMPA has been highlighted in a series of experiments showing a critical role in learning, cognition and mood control, all functions that require neuroplasticity.  Interestingly, dysfunctional glutamatergic neurotransmission and impaired mTOR pathway have been associated with psychoses, cognitive impairment and depression, indicating the glutamate-mTOR mechanism as an appealing target for novel drug discovery.  In fact, drugs directly targeting the mTOR pathway are effective in controlling epilepsy in TS children, while some psychoactive agents such as ketamine or nicotine were shown to exert their neuroplastic and behavioral effects via mTOR activation.   In this work we will review the data available indicating the AMPA receptor-mediated activation of mTOR on specific neuronal networks as a possible critical mechanism in controlling the long term manifestations of psychotic, cognitive- and mood-related symptoms.

Title: Therapeutic targeting of mTOR in T-ALL: an update
Authors: Camilla Evangelisti 1,2§, Francesca Charini 1,2§, James A. McCubrey3 and Alberto M. Martelli 4*
1    CNR Istituto di Genetica Molecolare, Unità di Bologna, Bologna, Italy; [email protected], [email protected]
2    Istituto Ortopedico Rizzoli, Bologna, Italy;
3    Department of Microbiology & Immunology, Brody School of Medcine, East Carolina University, Greenville, NC, USA; [email protected]
4     Department of Biomedical and Neuromotor Science, University of Bologna, Italy; [email protected]
§  Equally contributed
*Correspondence: [email protected]; Tel.: +39-051-209-1580
Abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood malignancy that arises from clonal expansion of transformed T-cell precursors. Although T-ALL prognosis has significantly improved due to the development of chemotherapeutic protocols, primary drug-resistant and relapsed patients still display a dismal outcome. In addition, life-long irreversible late effects from conventional therapy are a growing problem for leukemia survivors. Therefore, novel targeted therapies are urgently required to inprove the prognosis of high-risk patients. Mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. These two complexes regulates 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 that drives tumor cell proliferation, survival, metabolic transformation and metastatic potential. Promising preclinical studies using mTOR inhibitors 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.


Title: Targeting the mTOR and PI3K/Akt Signaling pathway as a Therapeutic Strategy for Human Chronic Skin Diseases: A Concise Update and Perspective.
Authors: Md Rafi Anwar1, Sergette Banang-Mbeumi1,2, Jean Fotie3, and Jean Christopher Chamcheu1
1Department of Basic Pharmaceutical Sciences, School of Pharmacy, College of Health and Pharmaceutic Sciences, University of Louisiana at Monroe, Monroe, LA 71209-0497, USA;
2Research and Innovation Center, POHOFI Inc., P.O. Box 44067, Madison, WI 53744, USA;
3Department of Chemistry and Physics, Southeastern Louisiana University, SLU 10878, Hammond, LA 70402-0878, USA.
Corresponding author: [email protected]
Summary: Chronic disorders of the skin and its appendages are amongst the most common heterogeneous and often incurable human diseases. Some exist with identified gene mutations, and dysregulation of key homeostatic and intracellular signalings, including epidermal differentiation, immune system, sonic hedgehog and Wnt/β-catenin. These generally constitute major public health problems and are typically associated with poor treatment outcomes. The mammalian target of rapamycin (mTOR), phosphatidylinositiol 3-kinase (PI3K), and protein kinase B (AKT) (mTOR/PI3K/AKT) signaling pathway critically controls key cellular responses such as cell growth and proliferation, survival, migration and metabolism. The past decades have increasingly recognized that components of the mTOR/PI3K/AKT signaling are frequently dysregulated via constitutive activation and associated with genetic/epigenetic alterations in a number of chronic inflammatory and hyperproliferative cutaneous diseases and malignancies, including psoriasis, atopic dermatitis, acnes, wounds, melanoma and non-melanoma skin cancers etc. Thus, an enhanced understanding of the molecular and genetic basis of skin dysfunction in chronic cutaneous disorders may provide novel leads for the development of promising therapeutic strategies for affected patients. This review will summarize recent advances in the role of mTOR/PI3K/AKT and targets in a broad spectrum of chronic dermatological diseases. Naturally occurring bioactive molecules including nutraceuticals and synthetic analogs that have shown promise as potential treatment for skin disorders targeting mTOR/PI3K/AKT signaling pathway will also be discussed, with a particular attention given to the implications of these approaches for translational clinical therapy.

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