CA125 (MUC16) tumor antigen selectively modulates the sensitivity of ovarian cancer cells to genotoxic drug-induced apoptosis.

OBJECTIVE: Little is known about the biological functions of CA125/MUC16 tumor antigen. Here, we examined the role of CA125/MUC16 in regulating the sensitivity of epithelial ovarian carcinoma (EOC) cells to different drugs.
METHODS: An endoplasmic reticulum targeted single-chain antibody (scFv) was used to down-regulate cell surface expression of CA125/MUC16 in NIH:OVCAR3 cells and the C-terminal domain (CTD) of MUC16 was ectopically expressed in CA125-negative SKOV3 cells. Sensitivity to genotoxic agents and to inhibitors of microtubule depolymerization was examined in NIH:OVCAR3 and SKOV3 cell sublines. Cell viability was determined by XTT assay, apoptosis by propidium iodide staining and caspase activation by Western blot and fluorogenic assay.
RESULTS: Down-regulation of cell surface MUC16 decreases cisplatin IC(50) by 5-fold in NIH:OVCAR3 cells but does not affect paclitaxel IC(50). We found that the sensitivity to other genotoxic agents such as cyclophosphamide, doxorubicine and etoposide was also increased by down-regulation of MUC16. Caspase-9 and caspase-3 activation also significantly augmented in cisplatin-treated NIH:OVCAR3 cells expressing the anti-MUC16 scFv. Ectopic expression of MUC16 CTD has the opposite effect. Cisplatin sensitivity and caspases activation are decreased by the ectopic expression of MUC16 CTD in SKOV3 cells.
CONCLUSIONS: CA125/MUC16 selectively modulates the sensitivity of EOC cells to genotoxic agents. The MUC16 CTD appears to be sufficient to promote cisplatin resistance.