The mechanism of exogenous IL-8-caused cisplatin and paclitaxel resistance of ovarian cancer cells and its related signal transduction pathways

Abstract：In this study, we aimed to discover the mechanism of cisplatin and paclitaxel resistance caused by exogenous IL-8 in ovarian cancer cells and its related signal pathways. Based on our previous studies, the effect of exogenous IL-8 on the sensitivity to cisplatin and paclitaxel in ovarian cancer cells was investigated. Meanwhile, we also investigated the mechanism of cisplatin and paclitaxel resistance caused by exogenous IL-8 in ovarian cancer cells and its related signal pathways. A2780, which do not express IL-8 and sensitive to cisplatin and paclitaxel, and SKOV-3 cells, which constitutively express high levels of IL-8 and resistant to cisplatin and paclitaxel, are suitable models for this study. We found that pretreatment of A2780 cells with IL-8 caused 6.07-fold and 7.23-fold increase in resistance to cisplatin and paclitaxel, respectively, whereas SKOV-3 cells exhibited 8.22-fold and 9.03- fold increase, respectively. IL-8 enhanced the expression of drug resistance-associated gene MDR1 and apoptosis-inhibiting genes (Bcl-2, Bcl-xL and XIAP) in A2780 and SKOV-3 cells. Pretreatment of A2780 cells with MEK1/2 or PI3K inhibitors blocked IL-8-induced cisplatin and paclitaxel resistance. These data suggest that IL-8 may confer cisplatin and paclitaxel resistance in ovarian cancer cells by increasing expression of drug resistance-associated gene MDR1 and apoptosis-in-hibiting genes Bcl-2, Bcl-xL and XIAP. These activity of IL-8 is dependent on Ras/Raf/MEK/MAPK and PI3K/Akt signal transduction pathways.