Chemotherapy resistance induced by interleukin-6 in ovarian cancer cells and its signal transduction pathways / 中华妇产科杂志

ABSTRACT

Objective To study the mechanism of chemotherapy resistance caused by interleukin-6 (IL-6) in ovarian cancer cells and its related signal pathways. Methods Ovarian cancer cell lines A2780(IL-6 receptor positive, while non-IL-6-expressing and cisplatin/paclitaxel-responsive) and SKOV3 cell lines( overexpressing of IL-6 receptor and IL-6 and cisplatin/paclitaxel-resistant) were suitable models for this study. The effect of exogenous (a short period of treatment with recombination IL-6) and endogenous IL-6(by transfecting with plasmid encoding for sense IL-6 ) in A2780 cells or deleting of endogenous IL-6expression in SKOV3 cells (by transfecting with plasmid encoding for antisense IL-6) on the sensitivity to cisplatin and paclitaxel was investigated. Meanwhile, the mechanism of chemotherapy resistance caused by IL-6 in ovarian cancer cells and its related signal pathways were also analyzed. Results We found that both exogenous and endogenous IL-6 induce cisplatin and paclitaxel resistance in non-IL-6-expressing A2780 cells (the resistance multiple to cisplatin and paclitaxel was exogenous, 6. 25 and 7.31; endogenous, 7. 13 -8. 34 and 7. 61 - 10. 70), while deleting of endogenous IL-6 expression in IL-6-overexpressing SKOV3 cells promotes its sensitivity to anticancer drugs ( the resistance multiple to cisplatin and paclitaxel was 0. 15 and 0. 10, 0. 10 and 0. 08). IL-6 significantly up-regulated the expression levels of mRNA and protein of drug resistance-associated genes, MDR1 and GST-π, and apoptosis-inhibiting genes, bcl-2, bcl-xL and XIAP in a dose-dependent manner in A2780 cells. In accordance with this finding, the mRNA and protein levels of MDR1 and GST-π enhanced in sense IL-6-transfected A2780 cells, and reduced in antisense IL-6-transfected SKOV3 cells compared with the corresponding parental and control vector-transfected cells, which had no difference. It was found that PD98059 [ mitogen-activated protein kinase-extracellular signalregulated kinase (MEK) inhibitor ] and wortmannin [ phosphatidylinositol 3-kinase (PI3K) inhibitor ]significantly antagonized IL-6-induced phosphorylation of extracellular signal-regulated kinase ( ERK ) and protein kinase B (Akt), respectively, and both of them blocked IL-6-induced cisplatin and paclitaxel resistance and the inhibitory effects of PD98059 and wortmannin were dependent on its concentration.Conclusions These data suggest that IL-6-induced chemoresistance may be associated with increase of both drug resistance-associated genes ( MDR1 and GST-π) and apoptosis-inhibiting genes ( bcl-2, bcl-xL and XIAP), and activation of MEK/ERK and PL3K/Akt. Therefore, modulation of IL-6 expression or its related signaling pathway may be a promising strategy of treatment for drug-resistant ovarian cancer.