p38 MAPK–mediated upregulation of claudin-3 and claudin-4 by gemcitabine contributes to chemoresistance in ovarian cancer

Abstract

Chemotherapy is a primary therapeutic option in cancer treatment, but often associated with unwanted side effects and drug resistance. Claudin-3 (CLDN3) and claudin-4 (CLDN4) are essential components of tight junctions, frequently overexpressed in ovarian cancer, serve as potential therapeutic targets. In this study, we utilized flow cytometry, qPCR, Western blot, and animal experiments to investigate the regulation of CLDN3 and CLDN4 by chemotherapy drug, gemcitabine, in the ovarian cancer cell line A2780. We reported that gemcitabine can induce expression of CLDN3 and CLDN4 in ovarian cancer cells. Mechanistically, we showed that gemcitabine induces expression of CLDN3 and CLDN4 through p38 MAP kinase mediated transcriptional regulation. Overexpression of CLDN3 or CLDN4 functionally protected A2780 ovarian cancer from gemcitabine induced cell killing. It appears that gemcitabine induced expression of CLDN3/4 is a chemoresistance mechanism for cancer cells. Gemcitabine-induced upregulation of CLDN3/4 suggests that ovarian cancer cells may be more effectively targeted using claudin-3/4-specific antibodies or antibody-drug conjugates (ADCs) in combination with chemotherapy, which could have clinical implications for ovarian cancer treatment in the future.