CXCL2-mediated ATR/CHK1 Signaling Pathway and Platinum Resistance in Epithelial Ovarian Cancer

Abstract

Tumor microenvironment and chemokines play a significant role in cancer chemoresistance. This study was designed to reveal the important role of CXCL2 in platinum resistance in epithelial ovarian cancer (EOC). Differently expressed (DE) genes were screen out based on analysis of GSE114206 dataset in GEO database. The expression of DE chemokines was further validated in platinum- resistant and sensitive EOC. Cell viability assay and cell apoptosis assay were performed to explore the roles of CXCL2 in EOC. Cell stemness characteristics and the signaling pathway regulated by CXCL2 were also investigated in this study. As the results showed, CXCL2 was identified up-regulated in platinum-resistant EOC. The functional assays showed overexpressing CXCL2 or co-culturing with recombinant human CXCL2 promoted cell resistance to cisplatin. Conversely, knocking down CXCL2 or co-culturing with neutralizing antibody to CXCL2 increased cell response to cisplatin. CXCL2 overexpressing maintained cell stemness and activated ATR/CHK1 signaling pathway in EOC. Moreover, we further demonstrated that CXCL2-mediated resistance to cisplatin could be saved by SB225002, the inhibitor of CXCL2 receptor, as well as be rescued by SAR-020106, the inhibitor of ATR/CHK1 signaling pathway. This study identified a CXCL2-mediated mechanism in EOC platinum resistance. Our findings provided a novel target for chemoresistance prevention in EOC.