In:
The FEBS Journal, Wiley, Vol. 281, No. 1 ( 2014-01), p. 115-128
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 SGC 7901 and BGC 823 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 (sh RNA ) vectors and the small‐molecule inhibitor YM 155, or inhibition of survivin function using a recombinant cell‐permeable dominant‐negative survivin protein (d NS ur9), promoted CDDP ‐induced apoptosis. CDDP ‐resistant sub‐lines generated from the parental SGC 7901 and BGC 823 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 (p AKT ). 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.
Type of Medium:
Online Resource
ISSN:
1742-464X
,
1742-4658
DOI:
10.1111/febs.2013.281.issue-1
Language:
English
Publisher:
Wiley
Publication Date:
2014
detail.hit.zdb_id:
2172518-4
SSG:
12
