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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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      Most cited references 137

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      AKT/PKB signaling: navigating downstream.

      The serine/threonine kinase Akt, also known as protein kinase B (PKB), is a central node in cell signaling downstream of growth factors, cytokines, and other cellular stimuli. Aberrant loss or gain of Akt activation underlies the pathophysiological properties of a variety of complex diseases, including type-2 diabetes and cancer. Here, we review the molecular properties of Akt and the approaches used to characterize its true cellular targets. In addition, we discuss those Akt substrates that are most likely to contribute to the diverse cellular roles of Akt, which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration.
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        Mutational landscape and significance across 12 major cancer types

        The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known(forexample, mitogen-activatedprotein kinase, phosphatidylinositol-3-OH kinase,Wnt/β-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the numberof driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.
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          COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer

          COSMIC (http://www.sanger.ac.uk/cosmic) curates comprehensive information on somatic mutations in human cancer. Release v48 (July 2010) describes over 136 000 coding mutations in almost 542 000 tumour samples; of the 18 490 genes documented, 4803 (26%) have one or more mutations. Full scientific literature curations are available on 83 major cancer genes and 49 fusion gene pairs (19 new cancer genes and 30 new fusion pairs this year) and this number is continually increasing. Key amongst these is TP53, now available through a collaboration with the IARC p53 database. In addition to data from the Cancer Genome Project (CGP) at the Sanger Institute, UK, and The Cancer Genome Atlas project (TCGA), large systematic screens are also now curated. Major website upgrades now make these data much more mineable, with many new selection filters and graphics. A Biomart is now available allowing more automated data mining and integration with other biological databases. Annotation of genomic features has become a significant focus; COSMIC has begun curating full-genome resequencing experiments, developing new web pages, export formats and graphics styles. With all genomic information recently updated to GRCh37, COSMIC integrates many diverse types of mutation information and is making much closer links with Ensembl and other data resources.
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            Author and article information

            Affiliations
            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.

            Journal
            Mol Pharmacol
            Mol. Pharmacol
            molpharm
            Mol Pharmacol
            MolPharm
            Molecular Pharmacology
            The American Society for Pharmacology and Experimental Therapeutics (Bethesda, MD )
            0026-895X
            1521-0111
            July 2018
            July 2018
            July 2018
            : 94
            : 1
            : 784-792
            29769245
            5994485
            MOL_112268
            10.1124/mol.118.112268
            Copyright © 2018 by The Author(s)

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

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            Figures: 1, Tables: 2, Equations: 0, References: 138, Pages: 9
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