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      Low Concentration of Withaferin a Inhibits Oxidative Stress-Mediated Migration and Invasion in Oral Cancer Cells

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          Abstract

          Withaferin A (WFA) has been reported to inhibit cancer cell proliferation based on high cytotoxic concentrations. However, the low cytotoxic effect of WFA in regulating cancer cell migration is rarely investigated. The purpose of this study is to investigate the changes in migration and mechanisms of oral cancer Ca9-22 cells after low concentrations of WFA treatment. WFA under 0.5 μM at 24 h treatment shows no cytotoxicity to oral cancer Ca9-22 cells (~95% viability). Under this condition, WFA triggers reactive oxygen species (ROS) production and inhibits 2D (wound healing) and 3D cell migration (transwell) and Matrigel invasion. Mechanically, WFA inhibits matrix metalloproteinase (MMP)-2 and MMP-9 activities but induces mRNA expression for a group of antioxidant genes, such as nuclear factor, erythroid 2-like 2 ( NFE2L2), heme oxygenase 1 ( HMOX1), glutathione-disulfide reductase ( GSR), and NAD(P)H quinone dehydrogenase 1 ( NQO1)) in Ca9-22 cells. Moreover, WFA induces mild phosphorylation of the mitogen-activated protein kinase (MAPK) family, including extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 expression. All WFA-induced changes were suppressed by the presence of ROS scavenger N-acetylcysteine (NAC). Therefore, these results suggest that low concentration of WFA retains potent ROS-mediated anti-migration and -invasion abilities for oral cancer cells.

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          Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis.

          Molecular, genetic and pathological evidence suggests that deficits in GABAergic parvalbumin-positive interneurons contribute to schizophrenia pathophysiology through alterations in the brain's excitation-inhibition balance that result in impaired behaviour and cognition. Although the factors that trigger these deficits are diverse, there is increasing evidence that they converge on a common pathological hub that involves NMDA receptor hypofunction and oxidative stress. These factors have been separately linked to schizophrenia pathogenesis, but evidence now suggests that they are mechanistically interdependent and contribute to a common schizophrenia-associated pathology.
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            Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002.

            The immunosuppressant, rapamycin, inhibits cell growth by interfering with the function of a novel kinase, termed mammalian target of rapamycin (mTOR). The putative catalytic domain of mTOR is similar to those of mammalian and yeast phosphatidylinositol (PI) 3-kinases. This study demonstrates that mTOR is a component of a cytokine-triggered protein kinase cascade leading to the phosphorylation of the eukaryotic initiation factor-4E (eIF-4E) binding protein, PHAS-1, in activated T lymphocytes. This event promotes G1 phase progression by stimulating eIF-4E-dependent translation initiation. A mutant YAC-1 T lymphoma cell line, which was selected for resistance to the growth-inhibitory action of rapamycin, was correspondingly resistant to the suppressive effect of this drug on PHAS-1 phosphorylation. In contrast, the PI 3-kinase inhibitor, wortmannin, reduced the phosphorylation of PHAS-1 in both rapamycin-sensitive and -resistant T cells. At similar drug concentrations (0.1-1 microM), wortmannin irreversibly inhibited the serine-specific autokinase activity of mTOR. The autokinase activity of mTOR was also sensitive to the structurally distinct PI 3-kinase inhibitor, LY294002, at concentrations (1-30 microM) nearly identical to those required for inhibition of the lipid kinase activity of the mammalian p85-p110 heterodimer. These studies indicate that the signaling functions of mTOR, and potentially those of other high molecular weight PI 3-kinase homologs, are directly affected by cellular treatment with wortmannin or LY294002.
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              Redox regulation of cell migration and adhesion.

              Reactive oxygen species (ROS), particularly hydrogen peroxide, and the proteins that regulate them play important roles in the migration and adhesion of cells. Stimulation of cell surface receptors with growth factors and chemoattractants generates ROS, which relay signals from the cell surface to key signaling proteins inside the cell. ROS act within cells to promote migration and also in nonmigrating cells to influence the behavior of migrating cells. Hydrogen peroxide has also been suggested to act as a chemoattractant in its own right, drawing immune cells to wounds. We discuss recent progress made towards understanding how organisms use ROS, and to what degree they depend on them, during the related processes of cell migration and adhesion. Copyright © 2011. Published by Elsevier Ltd.
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                Author and article information

                Journal
                Biomolecules
                Biomolecules
                biomolecules
                Biomolecules
                MDPI
                2218-273X
                17 May 2020
                May 2020
                : 10
                : 5
                : 777
                Affiliations
                [1 ]Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; u107500035@ 123456kmu.edu.tw
                [2 ]Department of Radiation Oncology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; reyata@ 123456kmu.edu.tw
                [3 ]Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
                [4 ]Division of Breast Surgery and Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan; swfuon@ 123456kmu.edu.tw
                [5 ]Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; wyy@ 123456kmu.edu.tw (Y.-Y.W.); yuanssf@ 123456kmu.edu.tw (S.-S.F.Y.)
                [6 ]School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
                [7 ]Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
                [8 ]Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
                [9 ]Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; kevintseng192@ 123456sjtu.edu.cn
                [10 ]Department of Radiation Oncology, Chi-Mei Foundation Medical Center, Tainan 71004, Taiwan
                [11 ]School of Medicine, Taipei Medical University, Taipei 11031, Taiwan
                [12 ]Chung Hwa University Medical Technology, Tainan 71703, Taiwan
                [13 ]Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
                [14 ]Department of Biomedical Science and Environmental Biology, College of Life Sciences, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
                Author notes
                [* ]Correspondence: 8508a6@ 123456mail.chimei.org.tw (L.-C.L.); changhw@ 123456kmu.edu.tw (H.-W.C.); Tel.: +886-6-281-2811 (ext. 53501) (L.-C.L.); +886-7-312-1101 (ext. 2691) (H.-W.C.)
                Author information
                https://orcid.org/0000-0002-4753-788X
                https://orcid.org/0000-0003-0068-2366
                Article
                biomolecules-10-00777
                10.3390/biom10050777
                7277689
                32429564
                1cdfeda3-f375-4342-b07b-689f7da2c108
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 February 2020
                : 15 May 2020
                Categories
                Article

                withaferin a,oral cancer,oxidative stress,migration,invasion,matrix metalloproteinases,antioxidant signaling

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