title: Up-regulation of survivin by AKT and hypoxia-inducible factor 1α contributes to cisplatin resistance in gastric cancer.
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.
authors.affiliation: Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, China.
authors.forename: Xue-Pu
authors.initials: XP
authors.lastname: Sun
authors.forename: Xuesong
authors.initials: X
authors.lastname: Dong
authors.forename: Lele
authors.initials: L
authors.lastname: Lin
authors.forename: Xian
authors.initials: X
authors.lastname: Jiang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wei
authors.forename: Bo
authors.initials: B
authors.lastname: Zhai
authors.forename: Bo
authors.initials: B
authors.lastname: Sun
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Wang
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Krissansen
authors.forename: Haiquan
authors.initials: H
authors.lastname: Qiao
authors.forename: Xueying
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077022:Survivin; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051034:Inhibitor of Apoptosis Proteins; D012333:RNA, Messenger; D000077022:Survivin; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin
keywords: AKT; cisplatin; gastric cancer; hypoxia-inducible factor-1α; survivin