Autocrine production of interleukin-8 confers cisplatin and paclitaxel resistance in ovarian cancer cells.

It has been widely reported that interleukin-8 (IL-8) is overexpressed in ovarian cyst fluid, ascites, serum, and tumor tissue from ovarian cancer (OVCA) patients, and elevated IL-8 expression correlates with a poor final outcome and chemosensitivity. However, the role of IL-8 expression in the acquisition of the chemoresistance phenotype and the underlining mechanisms of drug resistance in OVCA cells are not yet fully understood. Here we show that both exogenous (a relatively short period of treatment with recombination IL-8) and endogenous IL-8 (by transfecting with plasmid encoding for sense IL-8) induce cisplatin and paclitaxel resistance in non-IL-8-expressing A2780 cells, while deleting of endogenous IL-8 expression in IL-8-overexpressing SKOV-3 cells (by transfecting with plasmid encoding for antisense IL-8) promotes the sensitivity of these cells to anticancer drugs. IL-8-mediated resistance of OVCA cells exhibits decreased proteolytic activation of caspase-3. Meanwhile, the further study demonstrates that the chemoresistance caused by IL-8 is associated with increased expression of both multidrug resistance-related genes (MDR1) and apoptosis inhibitory proteins (Bcl-2, Bcl-xL, and XIAP), as well as activation of PI3K/Akt and Ras/MEK/ERK signaling. Therefore, modulation of IL-8 expression or its related signaling pathway may be a promising strategy of treatment for drug-resistant OVCA.