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      Redox regulation in tumor cell epithelial–mesenchymal transition: molecular basis and therapeutic strategy

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          Abstract

          Epithelial–mesenchymal transition (EMT) is recognized as a driving force of cancer cell metastasis and drug resistance, two leading causes of cancer recurrence and cancer-related death. It is, therefore, logical in cancer therapy to target the EMT switch to prevent such cancer metastasis and recurrence. Previous reports have indicated that growth factors (such as epidermal growth factor and fibroblast growth factor) and cytokines (such as the transforming growth factor beta (TGF-β) family) are major stimulators of EMT. However, the mechanisms underlying EMT initiation and progression remain unclear. Recently, emerging evidence has suggested that reactive oxygen species (ROS), important cellular secondary messengers involved in diverse biological events in cancer cells, play essential roles in the EMT process in cancer cells by regulating extracellular matrix (ECM) remodeling, cytoskeleton remodeling, cell–cell junctions, and cell mobility. Thus, targeting EMT by manipulating the intracellular redox status may hold promise for cancer therapy. Herein, we will address recent advances in redox biology involved in the EMT process in cancer cells, which will contribute to the development of novel therapeutic strategies by targeting redox-regulated EMT for cancer treatment.

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          Integrin-regulated FAK-Src signaling in normal and cancer cells.

          Integrins can alter cellular behavior through the recruitment and activation of signaling proteins such as non-receptor tyrosine kinases including focal adhesion kinase (FAK) and c-Src that form a dual kinase complex. The FAK-Src complex binds to and can phosphorylate various adaptor proteins such as p130Cas and paxillin. In normal cells, multiple integrin-regulated linkages exist to activate FAK or Src. Activated FAK-Src functions to promote cell motility, cell cycle progression and cell survival. Recent studies have found that the FAK-Src complex is activated in many tumor cells and generates signals leading to tumor growth and metastasis. As both FAK and Src catalytic activities are important in promoting VEGF-associated tumor angiogenesis and protease-associated tumor metastasis, support is growing that FAK and Src may be therapeutically relevant targets in the inhibition of tumor progression.
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            Tight junctions: from simple barriers to multifunctional molecular gates.

            Epithelia and endothelia separate different tissue compartments and protect multicellular organisms from the outside world. This requires the formation of tight junctions, selective gates that control paracellular diffusion of ions and solutes. Tight junctions also form the border between the apical and basolateral plasma-membrane domains and are linked to the machinery that controls apicobasal polarization. Additionally, signalling networks that guide diverse cell behaviours and functions are connected to tight junctions, transmitting information to and from the cytoskeleton, nucleus and different cell adhesion complexes. Recent advances have broadened our understanding of the molecular architecture and cellular functions of tight junctions.
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              Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways.

              Mitogen-activated protein (MAP) kinase cascades are activated in response to various extracellular stimuli, including growth factors and environmental stresses. A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. Overexpression of ASK1 induced apoptotic cell death, and ASK1 was activated in cells treated with tumor necrosis factor-alpha (TNF-alpha). Moreover, TNF-alpha-induced apoptosis was inhibited by a catalytically inactive form of ASK1. ASK1 may be a key element in the mechanism of stress- and cytokine-induced apoptosis.
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                Author and article information

                Journal
                Signal Transduct Target Ther
                Signal Transduct Target Ther
                Signal Transduction and Targeted Therapy
                Nature Publishing Group
                2095-9907
                2059-3635
                18 August 2017
                2017
                : 2
                : 17036
                Affiliations
                [1 ]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu, China
                [2 ]Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy , Chengdu, China
                [3 ]Department of Biochemistry and Molecular Biology, Monash University , Clayton, Victoria, Australia
                Author notes
                [4]

                These authors contributed equally to this work.

                Article
                sigtrans201736
                10.1038/sigtrans.2017.36
                5661624
                29263924
                12124079-b564-4cb7-a380-bd0a19285841
                Copyright © 2017 The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 31 December 2016
                : 25 April 2017
                : 25 April 2017
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                Review Article

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