N1-guanyl-1,7-diaminoheptane sensitizes bladder cancer cells to doxorubicin by preventing epithelial–mesenchymal transition through inhibition of eukaryotic translation initiation factor 5A2 activation

Authors

  • Jinsong Yang,

    Corresponding author
    1. Department of Radiation Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
    • Correspondence

      Jinsong Yang, Department of Radiation Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang 310003, China.

      Tel.: +86-571-87783609; Fax: +86-571-87783609; E-mail: yangjszju@163.com

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  • Haogang Yu,

    1. Department of Radiation Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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  • Mo Shen,

    1. Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medicine University, Wenzhou, Zhejiang, China
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  • Wei Wei,

    1. Department of Radiation Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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  • Lihong Xia,

    1. Department of Radiation Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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  • Peng Zhao

    1. Department of Radiation Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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  • Traditional Chinese Medicine Science Research Funds Program of Zhejiang (2013ZA077); Natural Science Funds of Zhejiang (Y2110555); National 973 Basic Research Program of China (2013CB911300).

Abstract

Drug resistance greatly reduces the efficacy of doxorubicin-based chemotherapy in bladder cancer treatment; however, the underlying mechanisms are poorly understood. We aimed to investigate whether N1-guanyl-1,7-diaminoheptane (GC7), which inhibits eukaryotic translation initiation factor 5A2 (eIF5A2) activation, exerts synergistic cytotoxicity with doxorubicin in bladder cancer, and whether eIF5A2 is involved in chemoresistance to doxorubicin-based bladder cancer treatment. BIU-87, J82, and UM-UC-3 bladder cancer cells were transfected with eIF5A2 siRNA or negative control siRNA before incubation with doxorubicin alone or doxorubicin plus GC7 for 48 h. Doxorubicin cytotoxicity was enhanced by GC7 in BIU-87, J82, and UM-UC-3 cells. It significantly inhibited activity of eIF5A2, suppressed doxorubicin-induced epithelial–mesenchymal transition in BIU-87 cells, and promoted mesenchymal–epithelial transition in J82 and UM-UC-3 cells. Knockdown of eIF5A2 sensitized bladder cancer cells to doxorubicin, prevented doxorubicin-induced EMT in BIU-87 cells, and encouraged mesenchymal–epithelial transition in J82 and UM-UC-3 cells. Combination therapy with GC7 may enhance the therapeutic efficacy of doxorubicin in bladder cancer by inhibiting eIF5A2 activation and preventing epithelial–mesenchymal transition.

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