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
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
Manuscript Submission Information
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- cell signaling
- tuberous sclerosis
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.