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      PI3K/Akt/mTOR Signaling Pathway and the Biphasic Effect of Arsenic in Carcinogenesis

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          Abstract

          Arsenic is a naturally occurring, ubiquitous metalloid found in the Earth’s crust. In its inorganic form, arsenic is highly toxic and carcinogenic and is widely found across the globe and throughout the environment. As an International Agency for Research on Cancer–defined class 1 human carcinogen, arsenic can cause multiple human cancers, including liver, lung, urinary bladder, skin, kidney, and prostate. Mechanisms of arsenic-induced carcinogenesis remain elusive, and this review focuses specifically on the role of the PI3K/AKT/mTOR pathway in promoting cancer development. In addition to exerting potent carcinogenic responses, arsenic is also known for its therapeutic effects against acute promyelocytic leukemia. Current literature suggests that arsenic can achieve both therapeutic as well as carcinogenic effects, and this review serves to examine the paradoxical effects of arsenic, specifically through the PI3K/AKT/mTOR pathway. Furthermore, a comprehensive review of current literature reveals an imperative need for future studies to establish and pinpoint the exact conditions for which arsenic can, and through what mechanisms it is able to, differentially regulate the PI3K/AKT/mTOR pathway to maximize the therapeutic and minimize the carcinogenic properties of arsenic.

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          DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival.

          Timothy Peterson, Mathieu Laplante, Carson C. Thoreen … (2009)
          The mTORC1 and mTORC2 pathways regulate cell growth, proliferation, and survival. We identify DEPTOR as an mTOR-interacting protein whose expression is negatively regulated by mTORC1 and mTORC2. Loss of DEPTOR activates S6K1, Akt, and SGK1, promotes cell growth and survival, and activates mTORC1 and mTORC2 kinase activities. DEPTOR overexpression suppresses S6K1 but, by relieving feedback inhibition from mTORC1 to PI3K signaling, activates Akt. Consistent with many human cancers having activated mTORC1 and mTORC2 pathways, DEPTOR expression is low in most cancers. Surprisingly, DEPTOR is highly overexpressed in a subset of multiple myelomas harboring cyclin D1/D3 or c-MAF/MAFB translocations. In these cells, high DEPTOR expression is necessary to maintain PI3K and Akt activation and a reduction in DEPTOR levels leads to apoptosis. Thus, we identify a novel mTOR-interacting protein whose deregulated overexpression in multiple myeloma cells represents a mechanism for activating PI3K/Akt signaling and promoting cell survival.
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            Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks.

            Brian Magnuson, Bilgen Ekim, Diane C. Fingar (2012)
            The ribosomal protein S6K (S6 kinase) represents an extensively studied effector of the TORC1 [TOR (target of rapamycin) complex 1], which possesses important yet incompletely defined roles in cellular and organismal physiology. TORC1 functions as an environmental sensor by integrating signals derived from diverse environmental cues to promote anabolic and inhibit catabolic cellular functions. mTORC1 (mammalian TORC1) phosphorylates and activates S6K1 and S6K2, whose first identified substrate was rpS6 (ribosomal protein S6), a component of the 40S ribosome. Studies over the past decade have uncovered a number of additional S6K1 substrates, revealing multiple levels at which the mTORC1-S6K1 axis regulates cell physiology. The results thus far indicate that the mTORC1-S6K1 axis controls fundamental cellular processes, including transcription, translation, protein and lipid synthesis, cell growth/size and cell metabolism. In the present review we summarize the regulation of S6Ks, their cellular substrates and functions, and their integration within rapidly expanding mTOR (mammalian TOR) signalling networks. Although our understanding of the role of mTORC1-S6K1 signalling in physiology remains in its infancy, evidence indicates that this signalling axis controls, at least in part, glucose homoeostasis, insulin sensitivity, adipocyte metabolism, body mass and energy balance, tissue and organ size, learning, memory and aging. As dysregulation of this signalling axis contributes to diverse disease states, improved understanding of S6K regulation and function within mTOR signalling networks may enable the development of novel therapeutics.
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              Regulation of mTORC1 by PI3K signaling.

              Christian Dibble, Lewis Cantley (2015)
              The class I phosphoinositide 3-kinase (PI3K)-mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signaling network directs cellular metabolism and growth. Activation of mTORC1 [composed of mTOR, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8(mLST8), 40-kDa proline-rich Akt substrate (PRAS40), and DEP domain-containing mTOR-interacting protein (DEPTOR)] depends on the Ras-related GTPases (Rags) and Ras homolog enriched in brain (Rheb) GTPase and requires signals from amino acids, glucose, oxygen, energy (ATP), and growth factors (including cytokines and hormones such as insulin). Here we discuss the signal transduction mechanisms through which growth factor-responsive PI3K signaling activates mTORC1. We focus on how PI3K-dependent activation of Akt and spatial regulation of the tuberous sclerosis complex (TSC) complex (TSC complex) [composed of TSC1, TSC2, and Tre2-Bub2-Cdc16-1 domain family member 7 (TBC1D7)] switches on Rheb at the lysosome, where mTORC1 is activated. Integration of PI3K- and amino acid-dependent signals upstream of mTORC1 at the lysosome is detailed in a working model. A coherent understanding of the PI3K-mTORC1 network is imperative as its dysregulation has been implicated in diverse pathologies including cancer, diabetes, autism, and aging.
              Article 0 comments Cited 300 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Pharmacol
                Journal ID (iso-abbrev): Mol. Pharmacol
                Journal ID (hwp): molpharm
                Journal ID (pmc): Mol Pharmacol
                Journal ID (publisher-id): MolPharm
                Title: Molecular Pharmacology
                Publisher: The American Society for Pharmacology and Experimental Therapeutics (Bethesda, MD )
                ISSN (Print): 0026-895X
                ISSN (Electronic): 1521-0111
                Publication date (Print): July 2018
                Publication date (Electronic): July 2018
                Publication date PMC-release: July 2018
                Volume: 94
                Issue: 1
                Pages: 784-792
                Affiliations
                [1]Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York
                Author notes
                Address correspondence to: Max Costa, Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge, Tuxedo, NY 10987. E-mail: Max.Costa@ 123456nyumc.org
                [1]

                Q.Y.C. and M.C. contributed equally to this work.

                Article
                Publisher ID: MOL_112268
                DOI: 10.1124/mol.118.112268
                PMC ID: 5994485
                PubMed ID: 29769245
                SO-VID: c62466e0-1c92-442a-b6af-3101343329bd
                Copyright © Copyright © 2018 by The Author(s)
                License:

                This is an open access article distributed under the CC BY-NC Attribution 4.0 International license.

                History
                Date received : 22 February 2018
                Date accepted : 30 April 2018
                Page count
                Figures: 1, Tables: 2, Equations: 0, References: 138, Pages: 9
                Categories
                Subject: Minireview
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