Cisplatin-induced ERK1/2 activity promotes G1 to S phase progression which leads to chemoresistance of ovarian cancer cells

Abstract

The link between ERK1/2 activity and cisplatin cytotoxicity, in association with the cell cycle, in ovarian cancer cell lines resistant (A2780cis; SK-OV-3) and sensitive (A2780) to cisplatin was determined. We observed that cisplatin, at a low concentration enhanced the activation of ERK1/2 in A2780 cells and increased their accumulation in the S phase, resulting in low cytotoxicity. A high concentration of drug induced dephosphorylation and degradation of ERK1/2 and was extremely toxic, accumulating most of to these cells in the sub-G1 phase. The PD98059, pharmacological inhibitor of ERK1/2 activation, increased the cytotoxicity of cisplatin applied at a low concentration to A2780 cells (decreased ERK1/2 activity), causing shift of cell accumulation from the S to G1 phase. Surprisingly, PD98059 enhanced cell viability when a chemotherapeutic was used at high concentration, intensifying phosphorylation level of ERK1/2 and reversing cell cycle arrest in sub-G1 to promote the G1 and S phases. A2780cis cells demonstrated resistance to cisplatin with high ERK1/2 activity and accumulation of cells in the G1 and S phases. PD98059 sensitized resistant cells to drug toxicity during the first 24 hours of treatment, with blocked ERK1/2 phosphorylation and prevented progression from the G1 to S phase. SK-OV-3 resistant cells characterized with extremely high basal phosphorylation of ERK1/2, which wasn’t changed after exposure to cisplatin. Administration of PD98059 didn’t change the cytotoxicity of cisplatin in these cells. In conclusion, ERK1/2, activated by cisplatin, participates in the cell cycle progression from the G1 to S phase, enhancing cells’ survival and drug resistance.