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Mtor Signaling in Metabolism and Cancer mTOR Signaling in mTOR Metabolism and Cancer • Shile Huang mTOR Signaling in Metabolism and Cancer Edited by Shile Huang Printed Edition of the Special Issue Published in Cells www.mdpi.com/journal/cells mTOR Signaling in Metabolism and Cancer mTOR Signaling in Metabolism and Cancer Editor Shile Huang MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade • Manchester • Tokyo • Cluj • Tianjin Editor Shile Huang Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center USA Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Cells (ISSN 2073-4409) (available at: https://www.mdpi.com/journal/cells/special issues/mTOR Signaling). For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03943-553-1 (Hbk) ISBN 978-3-03943-554-8 (PDF) c 2020 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Editor .............................................. vii Preface to “mTOR Signaling in Metabolism and Cancer” ...................... ix Shile Huang mTOR Signaling in Metabolism and Cancer Reprinted from: Cells 2020, 9, 2278, doi:10.3390/cells9102278 ..................... 1 Xiangyong Wei, Lingfei Luo and Jinzi Chen Roles of mTOR Signaling in Tissue Regeneration Reprinted from: Cells 2019, 8, 1075, doi:10.3390/cells8091075 ..................... 5 Ye Chen, Jacob Colello, Wael Jarjour and Song Guo Zheng Cellular Metabolic Regulation in the Differentiation and Function of Regulatory T Cells Reprinted from: Cells 2019, 8, 188, doi:10.3390/cells8020188 ...................... 29 Carolina Simioni, Alberto M. Martelli, Giorgio Zauli, Elisabetta Melloni and Luca M. Neri Targeting mTOR in Acute Lymphoblastic Leukemia Reprinted from: Cells 2019, 8, 190, doi:10.3390/cells8020190 ...................... 41 Simone Mirabilii, Maria Rosaria Ricciardi and Agostino Tafuri mTOR Regulation of Metabolism in Hematologic Malignancies Reprinted from: Cells 2020, 9, 404, doi:10.3390/cells9020404 ...................... 67 Fiona H. Tan, Yuchen Bai, Pierre Saintigny and Charbel Darido mTOR Signalling in Head and Neck Cancer: Heads Up Reprinted from: Cells 2019, 8, 333, doi:10.3390/cells8040333 ...................... 85 Sandra M. Ayuk and Heidi Abrahamse mTOR Signaling Pathway in Cancer Targets Photodynamic Therapy In Vitro Reprinted from: Cells 2019, 8, 431, doi:10.3390/cells8050431 ......................109 Jean Christopher Chamcheu, Tithi Roy, Mohammad Burhan Uddin, Sergette Banang-Mbeumi, Roxane-Cherille N. Chamcheu, Anthony L. Walker, Yong-Yu Liu and Shile Huang 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 Reprinted from: Cells 2019, 8, 803, doi:10.3390/cells8080803 ......................125 Jasmina Makarevi´c, Jochen Rutz, Eva Juengel, Sebastian Maxeiner, Jens Mani, Stefan Vallo, Igor Tsaur, Frederik Roos, Felix K.-H. Chun and Roman A. Blaheta HDAC Inhibition Counteracts Metastatic Re-Activation of Prostate Cancer Cells Induced by Chronic mTOR Suppression Reprinted from: Cells 2018, 7, 129, doi:10.3390/cells7090129 ......................159 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 Eribulin Synergistically Increases Anti-Tumor Activity of an mTOR Inhibitor by Inhibiting pAKT/pS6K/pS6 in Triple Negative Breast Cancer Reprinted from: Cells 2019, 8, 1010, doi:10.3390/cells8091010 .....................177 v About the Editor Shile Huang focuses on studying the role of mTOR signaling in human diseases, particularly in cancer. Since 1998, he has been studying how mTOR regulates cell survival, cell motility, and lymphangiogenesis; how some small molecules (e.g. curcumin, cryptotanshinone, dihydroartimisinin, and ciclopirox) act as anticancer agents; and how the heavy metal cadmium induces neuronal apoptosis. vii Preface to “mTOR Signaling in Metabolism and Cancer” The mechanistic/mammalian target of rapamycin (mTOR), a serine/threonine kinase, integrates environmental cues (hormones, growth factors, nutrients, oxygen, and energy), regulating cell growth, proliferation, survival and motility as well as metabolism. Dysregulation of mTOR signaling is implicated in a variety of disorders, such as cancer, obesity, diabetes, and neurodegenerative diseases. The articles published in this Special Issue reprint book 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. I am very thankful to all authors for their kind cooperation and wonderful contribution. I am also very grateful to the Managing Editor Beatty Teng for selection of this Special Issue as a reprint book. Shile Huang Editor ix cells Editorial mTOR Signaling in Metabolism and Cancer Shile Huang 1,2 1 Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA; [email protected]; Tel.: +1-318-675-7759 2 Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA Received: 10 October 2020; Accepted: 13 October 2020; Published: 13 October 2020 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 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. Keywords: mTOR; PI3K; Akt; tissue regeneration; regulatory T cells; tumor; photodynamic therapy The mechanistic/mammalian target of rapamycin (mTOR), a serine/threonine kinase, integrates environmental cues such as hormones, growth factors, nutrients, oxygen, and energy, regulating cell growth, proliferation, survival, motility and differentiation as well as metabolism (reviewed in [1,2]). Evidence has demonstrated that deregulated mTOR signaling is implicated in a variety of disorders, such as cancer, obesity, diabetes, and neurodegenerative diseases (reviewed in [1,2]). Current knowledge indicates that mTOR functions at least as two distinct complexes (mTORC1 and mTORC2) in mammalian cells. mTORC1 consists of mTOR, mLST8 (also termed G-protein β-subunit-like protein, GβL, a yeast homolog of LST8), raptor (regulatory-associated protein of mTOR), PRAS40 (proline-rich Akt substrate 40 kDa) and DEPTOR (DEP domain containing mTOR interacting protein), whereas mTORC2 is composed of mTOR, mLST8, rictor (rapamycin insensitive companion of mTOR), mSin1 (mammalian stress-activated protein kinase-interacting protein 1), protor (protein observed with rictor, also named PRR5, proline-rich protein 5), and DEPTOR [1,2]. mTORC1 regulates the phosphorylation or expression of p70 S6 kinase (S6K1), eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), lipin1, ULK1 (Unc-51 like autophagy activating kinase 1), TFEB (transcription factor EB), ATF4 (activating transcription factor 4), HIF1α (hypoxia-inducible factor 1 alpha), etc., and mediates the protein synthesis/turnover, lipid synthesis and nucleotide synthesis, thus controlling cell growth, proliferation, autophagy, and metabolism (reviewed in [1,2]). mTORC2 regulates the phosphorylation/activity of Akt, serum/glucocorticoid regulated kinase (SGK), protein kinase C (PKC), etc., thereby controlling cell migration, apoptosis and metabolism (reviewed in [1,2]). These findings not only reveal the crucial role of mTOR in physiology and pathology, but also reflect the complexity of the mTOR signaling network. 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 diverse types of cancer including hematologic malignancies, skin, prostate, breast, and head and neck cancer. Cells 2020, 9, 2278; doi:10.3390/cells91022781 www.mdpi.com/journal/cells Cells 2020, 9, 2278 Wei et al. (2019) discussed the role of mTOR signaling in the regeneration of tissues in the optic nerve, spinal cord, muscles, the liver and the intestine [3]. Activated mTOR enhances the regeneration of adult retinal ganglion cells after optic nerve injury. However, hyperactivation of mTOR in astrocytes promotes glial scar formation,
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