Up-regulation of survivin by AKT and hypoxia-inducible factor 1α contributes to cisplatin resistance in gastric cancer

Authors

  • Xue-Pu Sun,

    1. Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, China
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    • These authors contributed equally to this work.
  • Xuesong Dong,

    1. Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, China
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    • These authors contributed equally to this work.
  • Lele Lin,

    1. Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, China
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  • Xian Jiang,

    1. Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, China
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  • Zheng Wei,

    1. Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, China
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  • Bo Zhai,

    1. Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, China
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  • Bo Sun,

    1. Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, China
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  • Qiang Zhang,

    1. Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, China
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  • Xiaolong Wang,

    1. Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, China
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  • Hongchi Jiang,

    1. Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, China
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  • Geoffrey W. Krissansen,

    1. Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, the University of Auckland, New Zealand
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  • Haiquan Qiao,

    Corresponding author
    1. Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, China
    • Correspondence

      H. Qiao, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China

      Fax/Tel: +86 451 85555875 and

      X. Sun, Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, the University of Auckland, Auckland 1005, New Zealand

      Fax: +64 9 3737492

      Tel: +64 9 9235935

      E-mails: qiaohaiquan@hotmail.com; k.sun@auckland.ac.nz

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  • Xueying Sun

    Corresponding author
    1. Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, China
    2. Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, the University of Auckland, New Zealand
    • Correspondence

      H. Qiao, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China

      Fax/Tel: +86 451 85555875 and

      X. Sun, Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, the University of Auckland, Auckland 1005, New Zealand

      Fax: +64 9 3737492

      Tel: +64 9 9235935

      E-mails: qiaohaiquan@hotmail.com; k.sun@auckland.ac.nz

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Abstract

This study investigated the contribution of survivin and its upstream regulators, AKT and hypoxia-inducible factor 1α (HIF–1α), to the resistance of gastric cancer cells to cisplatin (CDDP). We found that over-expression of survivin increased the resistance of SGC7901 and BGC823 gastric cancer cells to CDDP. Its over-expression abrogated CDDP-induced inhibition of cell proliferation and CDDP-induced cell apoptosis. In contrast, down-regulation of survivin expression using small hairpin RNA (shRNA) vectors and the small-molecule inhibitor YM155, or inhibition of survivin function using a recombinant cell-permeable dominant-negative survivin protein (dNSur9), promoted CDDP-induced apoptosis. CDDP-resistant sub-lines generated from the parental SGC7901 and BGC823 cells by exposure to increasing concentrations of CDDP expressed higher levels of HIF–1α and survivin in response to hypoxia, and higher levels of phosphorylated AKT (pAKT). Specific inhibition of AKT reduced the expression of HIF–1α and survivin, whereas specific inhibition or depletion of HIF–1α reduced survivin expression but had no effect on the expression of phosphorylated AKT. The expression levels of survivin affected the therapeutic efficacy of CDDP in treating gastric tumors in mice. Specific inhibition of survivin, AKT and HIF–1α enhanced the sensitivity of CDDP-resistant cells to CDDP. Specific inhibition of survivin, AKT and HIF-1α synergized with CDDP to suppress the growth of gastric tumors that had been engineered to overexpress survivin. In summary, the results provide evidence that up-regulation of survivin by AKT and HIF–1α contributes to CDDP resistance, indicating that inhibition of these pathways may be a potential strategy for overcoming CDDP resistance in the treatment of gastric cancer.

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