Dysfunctional activity of classical DNA end-joining renders acquired resistance to carboplatin in human ovarian cancer cells.

ABSTRACT

Ovarian cancer is the deadliest gynecological malignancy worldwide. Although chemotherapy is required as the most standard treatment strategy for ovarian cancer, the survival rates are very low, largely because of high incidence of recurrence due to resistance to conventional surgery and genotoxic chemotherapies. Carboplatin-resistant ovarian cancer cells were generated by continuous treatment over six months. Carboplatin-resistance induced morphological alterations and promoted the rates of proliferation and migration of SKOV3 compared to the parental cells. Interestingly, carboplatin-resistant SKOV3 showed the high levels of γH2AX foci formed at the basal level, and the levels of γH2AX foci remained even after the recovery time, suggesting that the DNA damage response and repair machinery were severely attenuated by carboplatin-resistance. Surprisingly, the expression levels of XRCC4, a critical factor in non-homologous end joining (NHEJ) DNA repair, were significantly decreased in carboplatin-resistant SKOV3 compared with those in non-resistant controls. Furthermore, restoration of NHEJ in carboplatin-resistant SKOV3 by suppression of ABCB1 and/or AR re-sensitized carboplatin-resistant cells to genotoxic stress and reduced their proliferation ability. Our findings suggest that attenuation of the NHEJ DNA repair machinery mediated by resistance to genotoxic stress might be a critical cause of chemoresistance in patients with ovarian cancer.