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      The AKT1/NF-kappaB/Notch1/PTEN axis has an important role in chemoresistance of gastric cancer cells

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          Abstract

          The inherent resistance of tumors to DNA damage often limits the efficacy of chemotherapy. The aim of this work is to explore the potential mechanism for development of chemoresistance in gastric cancer. Our data revealed that AKT1 mRNA and protein expression were induced by doxorubicin (a chemotherapeutic agent); the doxorubicin-induced AKT1 expression and activation increased the binding of NF-kappaB on Notch1 DNA promoter and then promoted the Notch1 transcription and expression; enhanced expression of Notch1 further upregulated PTEN expression through CBF-1 binding to PTEN DNA promoter; and inhibition of AKT1 expression and activity sensitized the gastric cancer cell to doxorubicin treatment in cultured gastric cancer cell lines and xenograft nude mice gastric cancer model. Furthermore, our data demonstrated that both Notch1 and PTEN were absent or minimally expressed in gastric cancer tissue but abundant in paired normal gastric mucosa, and the expression of Notch1 correlated with that of PTEN. Together, these novel results suggested that a novel AKT1/NF-kappaB/Notch1/PTEN axis has an important role in the development of chemoresistance in gastric cancer. Notch1 has an anti-cancer role in gastric cancer.

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          Most cited references 36

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          Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy.

           S Fulda,  K-M Debatin (2006)
          Apoptosis or programmed cell death is a key regulator of physiological growth control and regulation of tissue homeostasis. One of the most important advances in cancer research in recent years is the recognition that cell death mostly by apoptosis is crucially involved in the regulation of tumor formation and also critically determines treatment response. Killing of tumor cells by most anticancer strategies currently used in clinical oncology, for example, chemotherapy, gamma-irradiation, suicide gene therapy or immunotherapy, has been linked to activation of apoptosis signal transduction pathways in cancer cells such as the intrinsic and/or extrinsic pathway. Thus, failure to undergo apoptosis may result in treatment resistance. Understanding the molecular events that regulate apoptosis in response to anticancer chemotherapy, and how cancer cells evade apoptotic death, provides novel opportunities for a more rational approach to develop molecular-targeted therapies for combating cancer.
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            Tenets of PTEN tumor suppression.

            Since its discovery as the elusive tumor suppressor gene at the frequently mutated 10q23 locus, PTEN has been identified as lost or mutated in several sporadic and heritable tumor types. A decade of work has established that PTEN is a nonredundant phosphatase that is essential for regulating the highly oncogenic prosurvival PI3K/AKT signaling pathway. This review discusses emerging modes of PTEN function and regulation, and speculates about how manipulation of PTEN function could be used for cancer therapy.
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              Regulation of PTEN transcription by p53.

              PTEN tumor suppressor is frequently mutated in human cancers and is a negative regulator of PI3'K/PKB/Akt-dependent cellular survival. Investigation of the human genomic PTEN locus revealed a p53 binding element directly upstream of the PTEN gene. Deletion and mutation analyses showed that this element is necessary for inducible transactivation of PTEN by p53. A p53-independent element controlling constitutive expression of PTEN was also identified. In contrast to p53 mutant cell lines, induction of p53 in primary and tumor cell lines with wild-type p53 increased PTEN mRNA levels. PTEN was required for p53-mediated apoptosis in immortalized mouse embryonic fibroblasts. Our results reveal a unique role for p53 in regulation of cellular survival and an interesting connection in tumor suppressor signaling.
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                Author and article information

                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group
                2041-4889
                October 2013
                10 October 2013
                1 October 2013
                : 4
                : 10
                : e847
                Affiliations
                [1 ]Department of Gastroenterology, Renmin Hospital of Wuhan Univeristy , 430060 Wuhan, China
                [2 ]Department of Gastroenterology, The First Hospital of Wuhan , 43000 Wuhan, China
                [3 ]Institute for Gastroenterology and Hepatology, Renmin Hospital of Wuhan Univeristy , 430060 Wuhan, China
                Author notes
                [* ]Department of Gastroenterology, Renmin Hospital of Wuhan University and Institute for Gastroenterology and Hepatology, Wuhan University , Jiefang Road 238, Wuhan 430060, China. Tel: +86 27 88041911 82135; Fax: +86 27 88042292; E-mail: yhg_rmhwh@ 123456163.com
                [4]

                These authors contributed equally to this work.

                Article
                cddis2013375
                10.1038/cddis.2013.375
                3824684
                24113181
                Copyright © 2013 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                Categories
                Original Article

                Cell biology

                akt1, nf-kappab, notch-1, pten, gastric cancer

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