The mechanism of cisplatin and paclitaxel resistance caused by endogenous IL-8 in ovarian cancer cells

This study aimed to discover the mechanism of cisplatin and paclitaxel resistance caused by endogenous interleukin-8(IL-8) in ovarian cancer cells and its related signal pathways.Based on our previous studies,A2780(non-IL-8-expressing and cisplatin/paclitaxel-responsive) and SKOV-3(IL-8-overexpressing and cisplatin/paclitaxel-resistant) cell lines were suitable models for this study.Then sense IL-8 or antisense IL-8 was stably transfected into A2780 and SKOV3 cells for detecting the effect of endogenous IL-8 on ovarian cancer cells resistance against cisplatin and paclitaxel.Meanwhile,we also analyzed the mechanism of chemotherapy resistance caused by IL-8 in ovarian cancer cells and its related signal pathways.We found that endogenous IL-8 could induce cisplatin and paclitaxel resistance in non-IL-8-expressing A2780 cells,while deletion of endogenous IL-8 expression in IL-8-overexpressing SKOV3 cells could recover the sensitivity of these cells to anticancer drugs.While IL-8 mediated chemotherapy resistance of ovarian cancer cells through decreasing proteolytic activation of caspase-3.Moreover,endogenous IL-8 significantly enhanced the expression of drug resistance-associated gene MDR1,and apoptosis-inhibiting genes Bcl-2,Bcl-xL,and XIAP in sense IL-8-transfected A2780 cells,but reduced in antisense IL-8-transfected SKOV3 cells compared with the corresponding parental and control vector-transfected cells.It also found that wortmannin(PI3K inhibitor) and PD98059(MEK1/2 inhibitor) could significantly antagonized IL-8-induced phosphorylation of Akt and ERK,respectively,and both of them blocked IL-8-induced cisplatin and paclitaxel resistance.Furthermore,the inhibitory effects of PD98059 and wortmannin were dependent on its concentration.These data suggest that IL-8-induced chemoresistance may be associated with the increase of both drug resistance-associated gene MDR1 and apoptosis-inhibiting genes Bcl-2,Bcl-xL and XIAP,as well as the activation of Raf /MEK/ERK and PI3K/Akt.Therefore,modulation of IL-8 expression or its related signaling pathway may be a promising strategy of treatment for drug-resistant ovarian cancer.