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Open AccessEditorial

mTOR Signaling in Metabolism and Cancer

by Shile Huang

Cells 2020, 9(10), 2278; https://doi.org/10.3390/cells9102278 - 13 Oct 2020

Cited by 46 | Viewed by 3705

Abstract

The mechanistic/mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a central regulator for human physiological activity. Deregulated mTOR signaling is implicated in a variety of disorders, such as cancer, obesity, diabetes, and neurodegenerative diseases. The papers published in this special issue summarize [...] Read more.

The mechanistic/mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a central regulator for human physiological activity. Deregulated mTOR signaling is implicated in a variety of disorders, such as cancer, obesity, diabetes, and neurodegenerative diseases. The papers published in this special issue summarize the current understanding of the mTOR pathway and its role in the regulation of tissue regeneration, regulatory T cell differentiation and function, and different types of cancer including hematologic malignancies, skin, prostate, breast, and head and neck cancer. The findings highlight that targeting the mTOR pathway is a promising strategy to fight against certain human diseases. Full article

(This article belongs to the Special Issue mTOR Signaling in Metabolism and Cancer)

Research

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15 pages, 2705 KiB

Open AccessArticle

Eribulin Synergistically Increases Anti-Tumor Activity of an mTOR Inhibitor by Inhibiting pAKT/pS6K/pS6 in Triple Negative Breast Cancer

by Wei Wen, Emily Marcinkowski, David Luyimbazi, Thehang Luu, Quanhua Xing, Jin Yan, Yujun Wang, Jun Wu, Yuming Guo, Dylan Tully, Ernest S. Han, Susan E. Yost, Yuan Yuan and John H. Yim

Cells 2019, 8(9), 1010; https://doi.org/10.3390/cells8091010 - 30 Aug 2019

Cited by 22 | Viewed by 4939

Abstract

Unlike other breast cancer subtypes, patients with triple negative breast cancer (TNBC) have poor outcomes and no effective targeted therapies, leaving an unmet need for therapeutic targets. Efforts to profile these tumors have revealed the PI3K/AKT/mTOR pathway as a potential target. Activation of [...] Read more.

Unlike other breast cancer subtypes, patients with triple negative breast cancer (TNBC) have poor outcomes and no effective targeted therapies, leaving an unmet need for therapeutic targets. Efforts to profile these tumors have revealed the PI3K/AKT/mTOR pathway as a potential target. Activation of this pathway also contributes to resistance to anti-cancer agents, including microtubule-targeting agents. Eribulin is one such microtubule-targeting agent that is beneficial in treating taxane and anthracycline refractory breast cancer. In this study, we compared the effect of eribulin on the PI3K/AKT/mTOR pathway with other microtubule-targeting agents in TNBC. We found that the phosphorylation of AKT was suppressed by eribulin, a microtubule depolymerizing agent, but activated by paclitaxel, a microtubule stabilizing agent. The combination of eribulin and everolimus, an mTOR inhibitor, resulted in an increased reduction of p-S6K1 and p-S6, a synergistic inhibition of cell survival in vitro, and an enhanced suppression of tumor growth in two orthotopic mouse models. These findings provide a preclinical foundation for targeting both the microtubule cytoskeleton and the PI3K/AKT/mTOR pathway in the treatment of refractory TNBC. Full article

(This article belongs to the Special Issue mTOR Signaling in Metabolism and Cancer)

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17 pages, 2804 KiB

Open AccessArticle

HDAC Inhibition Counteracts Metastatic Re-Activation of Prostate Cancer Cells Induced by Chronic mTOR Suppression

by Jasmina Makarević, Jochen Rutz, Eva Juengel, Sebastian Maxeiner, Jens Mani, Stefan Vallo, Igor Tsaur, Frederik Roos, Felix K.-H. Chun and Roman A. Blaheta

Cells 2018, 7(9), 129; https://doi.org/10.3390/cells7090129 - 1 Sep 2018

Cited by 19 | Viewed by 4817

Abstract

This study was designed to investigate whether epigenetic modulation by histone deacetylase (HDAC) inhibition might circumvent resistance towards the mechanistic target of rapamycin (mTOR) inhibitor temsirolimus in a prostate cancer cell model. Parental (par) and temsirolimus-resistant (res) PC3 prostate cancer cells were exposed [...] Read more.

This study was designed to investigate whether epigenetic modulation by histone deacetylase (HDAC) inhibition might circumvent resistance towards the mechanistic target of rapamycin (mTOR) inhibitor temsirolimus in a prostate cancer cell model. Parental (par) and temsirolimus-resistant (res) PC3 prostate cancer cells were exposed to the HDAC inhibitor valproic acid (VPA), and tumor cell adhesion, chemotaxis, migration, and invasion were evaluated. Temsirolimus resistance was characterized by reduced binding of PC3^res cells to endothelium, immobilized collagen, and fibronectin, but increased adhesion to laminin, as compared to the parental cells. Chemotaxis, migration, and invasion of PC3^res cells were enhanced following temsirolimus re-treatment. Integrin α and β receptors were significantly altered in PC3^res compared to PC3^par cells. VPA significantly counteracted temsirolimus resistance by down-regulating tumor cell–matrix interaction, chemotaxis, and migration. Evaluation of integrin expression in the presence of VPA revealed a significant down-regulation of integrin α5 in PC3^res cells. Blocking studies demonstrated a close association between α5 expression on PC3^res and chemotaxis. In this in vitro model, temsirolimus resistance drove prostate cancer cells to become highly motile, while HDAC inhibition reversed the metastatic activity. The VPA-induced inhibition of metastatic activity was accompanied by a lowered integrin α5 surface level on the tumor cells. Full article

(This article belongs to the Special Issue mTOR Signaling in Metabolism and Cancer)

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Review

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17 pages, 921 KiB

Open AccessReview

mTOR Regulation of Metabolism in Hematologic Malignancies

by Simone Mirabilii, Maria Rosaria Ricciardi and Agostino Tafuri

Cells 2020, 9(2), 404; https://doi.org/10.3390/cells9020404 - 11 Feb 2020

Cited by 14 | Viewed by 3806

Abstract

Neoplastic cells rewire their metabolism, acquiring a selective advantage over normal cells and a protection from therapeutic agents. The mammalian Target of Rapamycin (mTOR) is a serine/threonine kinase involved in a variety of cellular activities, including the control of metabolic processes. mTOR is [...] Read more.

Neoplastic cells rewire their metabolism, acquiring a selective advantage over normal cells and a protection from therapeutic agents. The mammalian Target of Rapamycin (mTOR) is a serine/threonine kinase involved in a variety of cellular activities, including the control of metabolic processes. mTOR is hyperactivated in a large number of tumor types, and among them, in many hematologic malignancies. In this article, we summarized the evidence from the literature that describes a central role for mTOR in the acquisition of new metabolic phenotypes for different hematologic malignancies, in concert with other metabolic modulators (AMPK, HIF1α) and microenvironmental stimuli, and shows how these features can be targeted for therapeutic purposes. Full article

(This article belongs to the Special Issue mTOR Signaling in Metabolism and Cancer)

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23 pages, 2314 KiB

Open AccessReview

Roles of mTOR Signaling in Tissue Regeneration

by Xiangyong Wei, Lingfei Luo and Jinzi Chen

Cells 2019, 8(9), 1075; https://doi.org/10.3390/cells8091075 - 12 Sep 2019

Cited by 88 | Viewed by 12045

Abstract

The mammalian target of rapamycin (mTOR), is a serine/threonine protein kinase and belongs to the phosphatidylinositol 3-kinase (PI3K)-related kinase (PIKK) family. mTOR interacts with other subunits to form two distinct complexes, mTORC1 and mTORC2. mTORC1 coordinates cell growth and metabolism in response to [...] Read more.

The mammalian target of rapamycin (mTOR), is a serine/threonine protein kinase and belongs to the phosphatidylinositol 3-kinase (PI3K)-related kinase (PIKK) family. mTOR interacts with other subunits to form two distinct complexes, mTORC1 and mTORC2. mTORC1 coordinates cell growth and metabolism in response to environmental input, including growth factors, amino acid, energy and stress. mTORC2 mainly controls cell survival and migration through phosphorylating glucocorticoid-regulated kinase (SGK), protein kinase B (Akt), and protein kinase C (PKC) kinase families. The dysregulation of mTOR is involved in human diseases including cancer, cardiovascular diseases, neurodegenerative diseases, and epilepsy. Tissue damage caused by trauma, diseases or aging disrupt the tissue functions. Tissue regeneration after injuries is of significance for recovering the tissue homeostasis and functions. Mammals have very limited regenerative capacity in multiple tissues and organs, such as the heart and central nervous system (CNS). Thereby, understanding the mechanisms underlying tissue regeneration is crucial for tissue repair and regenerative medicine. mTOR is activated in multiple tissue injuries. In this review, we summarize the roles of mTOR signaling in tissue regeneration such as neurons, muscles, the liver and the intestine. Full article

(This article belongs to the Special Issue mTOR Signaling in Metabolism and Cancer)

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33 pages, 7317 KiB

Open AccessEditor’s ChoiceReview

Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy

by Jean Christopher Chamcheu, Tithi Roy, Mohammad Burhan Uddin, Sergette Banang-Mbeumi, Roxane-Cherille N. Chamcheu, Anthony L. Walker, Yong-Yu Liu and Shile Huang

Cells 2019, 8(8), 803; https://doi.org/10.3390/cells8080803 - 31 Jul 2019

Cited by 133 | Viewed by 12040

Abstract

The mammalian or mechanistic target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) pathways regulate cell growth, differentiation, migration, and survival, as well as angiogenesis and metabolism. Dysregulation of these pathways is frequently associated with genetic/epigenetic alterations and predicts poor [...] Read more.

The mammalian or mechanistic target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) pathways regulate cell growth, differentiation, migration, and survival, as well as angiogenesis and metabolism. Dysregulation of these pathways is frequently associated with genetic/epigenetic alterations and predicts poor treatment outcomes in a variety of human cancers including cutaneous malignancies like melanoma and non-melanoma skin cancers. Recently, the enhanced understanding of the molecular and genetic basis of skin dysfunction in patients with skin cancers has provided a strong basis for the development of novel therapeutic strategies for these obdurate groups of skin cancers. This review summarizes recent advances in the roles of PI3K/Akt/mTOR and their targets in the development and progression of a broad spectrum of cutaneous cancers and discusses the current progress in preclinical and clinical studies for the development of PI3K/Akt/mTOR targeted therapies with nutraceuticals and synthetic small molecule inhibitors. Full article

(This article belongs to the Special Issue mTOR Signaling in Metabolism and Cancer)

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15 pages, 2355 KiB

Open AccessReview

mTOR Signaling Pathway in Cancer Targets Photodynamic Therapy In Vitro

by Sandra M. Ayuk and Heidi Abrahamse

Cells 2019, 8(5), 431; https://doi.org/10.3390/cells8050431 - 9 May 2019

Cited by 20 | Viewed by 5644

Abstract

The Mechanistic or Mammalian Target of Rapamycin (mTOR) is a major signaling pathway in eukaryotic cells belonging to the P13K-related kinase family of the serine/threonine protein kinase. It has been established that mTOR plays a central role in cellular processes and implicated in [...] Read more.

The Mechanistic or Mammalian Target of Rapamycin (mTOR) is a major signaling pathway in eukaryotic cells belonging to the P13K-related kinase family of the serine/threonine protein kinase. It has been established that mTOR plays a central role in cellular processes and implicated in various cancers, diabetes, and in the aging process with very poor prognosis. Inhibition of the mTOR pathway in the cells may improve the therapeutic index in cancer treatment. Photodynamic therapy (PDT) has been established to selectively eradicate neoplasia at clearly delineated malignant lesions. This review highlights recent advances in understanding the role or regulation of mTOR in cancer therapy. It also discusses how mTOR currently contributes to cancer as well as future perspectives on targeting mTOR therapeutically in cancer in vitro. Full article

(This article belongs to the Special Issue mTOR Signaling in Metabolism and Cancer)

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23 pages, 1580 KiB

Open AccessReview

mTOR Signalling in Head and Neck Cancer: Heads Up

by Fiona H. Tan, Yuchen Bai, Pierre Saintigny and Charbel Darido

Cells 2019, 8(4), 333; https://doi.org/10.3390/cells8040333 - 9 Apr 2019

Cited by 47 | Viewed by 6192

Abstract

The mammalian target of rapamycin (mTOR) signalling pathway is a central regulator of metabolism in all cells. It senses intracellular and extracellular signals and nutrient levels, and coordinates the metabolic requirements for cell growth, survival, and proliferation. Genetic alterations that deregulate mTOR signalling [...] Read more.

The mammalian target of rapamycin (mTOR) signalling pathway is a central regulator of metabolism in all cells. It senses intracellular and extracellular signals and nutrient levels, and coordinates the metabolic requirements for cell growth, survival, and proliferation. Genetic alterations that deregulate mTOR signalling lead to metabolic reprogramming, resulting in the development of several cancers including those of the head and neck. Gain-of-function mutations in EGFR, PIK3CA, and HRAS, or loss-of-function in p53 and PTEN are often associated with mTOR hyperactivation, whereas mutations identified from The Cancer Genome Atlas (TCGA) dataset that potentially lead to aberrant mTOR signalling are found in the EIF4G1, PLD1, RAC1, and SZT2 genes. In this review, we discuss how these mutant genes could affect mTOR signalling and highlight their impact on metabolic processes, as well as suggest potential targets for therapeutic intervention, primarily in head and neck cancer. Full article

(This article belongs to the Special Issue mTOR Signaling in Metabolism and Cancer)

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26 pages, 6435 KiB

Open AccessReview

Targeting mTOR in Acute Lymphoblastic Leukemia

by Carolina Simioni, Alberto M. Martelli, Giorgio Zauli, Elisabetta Melloni and Luca M. Neri

Cells 2019, 8(2), 190; https://doi.org/10.3390/cells8020190 - 21 Feb 2019

Cited by 44 | Viewed by 7716

Abstract

Acute Lymphoblastic Leukemia (ALL) is an aggressive hematologic disorder and constitutes approximately 25% of cancer diagnoses among children and teenagers. Pediatric patients have a favourable prognosis, with 5-years overall survival rates near 90%, while adult ALL still correlates with poorer survival. However, during [...] Read more.

Acute Lymphoblastic Leukemia (ALL) is an aggressive hematologic disorder and constitutes approximately 25% of cancer diagnoses among children and teenagers. Pediatric patients have a favourable prognosis, with 5-years overall survival rates near 90%, while adult ALL still correlates with poorer survival. However, during the past few decades, the therapeutic outcome of adult ALL was significantly ameliorated, mainly due to intensive pediatric-based protocols of chemotherapy. Mammalian (or mechanistic) target of rapamycin (mTOR) is a conserved serine/threonine kinase belonging to the phosphatidylinositol 3-kinase (PI3K)-related kinase family (PIKK) and resides in two distinct signalling complexes named mTORC1, involved in mRNA translation and protein synthesis and mTORC2 that controls cell survival and migration. Moreover, both complexes are remarkably involved in metabolism regulation. Growing evidence reports that mTOR dysregulation is related to metastatic potential, cell proliferation and angiogenesis and given that PI3K/Akt/mTOR network activation is often associated with poor prognosis and chemoresistance in ALL, there is a constant need to discover novel inhibitors for ALL treatment. Here, the current knowledge of mTOR signalling and the development of anti-mTOR compounds are documented, reporting the most relevant results from both preclinical and clinical studies in ALL that have contributed significantly into their efficacy or failure. Full article

(This article belongs to the Special Issue mTOR Signaling in Metabolism and Cancer)

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12 pages, 1245 KiB

Open AccessReview

Cellular Metabolic Regulation in the Differentiation and Function of Regulatory T Cells

by Ye Chen, Jacob Colello, Wael Jarjour and Song Guo Zheng

Cells 2019, 8(2), 188; https://doi.org/10.3390/cells8020188 - 21 Feb 2019

Cited by 30 | Viewed by 5584

Abstract

Regulatory T cells (Tregs) are essential for maintaining immune tolerance and preventing autoimmune and inflammatory diseases. The activity and function of Tregs are in large part determined by various intracellular metabolic processes. Recent findings have focused on how intracellular metabolism can shape the [...] Read more.

Regulatory T cells (Tregs) are essential for maintaining immune tolerance and preventing autoimmune and inflammatory diseases. The activity and function of Tregs are in large part determined by various intracellular metabolic processes. Recent findings have focused on how intracellular metabolism can shape the development, trafficking, and function of Tregs. In this review, we summarize and discuss current research that reveals how distinct metabolic pathways modulate Tregs differentiation, phenotype stabilization, and function. These advances highlight numerous opportunities to alter Tregs frequency and function in physiopathologic conditions via metabolic manipulation and have important translational implications. Full article

(This article belongs to the Special Issue mTOR Signaling in Metabolism and Cancer)

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