GDF15 promotes the resistance of epithelial ovarian cancer cells to gemcitabine via DHCR24-mediated cholesterol metabolism to elevate ABCB1 and ABCC1 levels in lipid rafts.

Abstract

Growth differentiation factor 15 (GDF15) is upregulated in most cases of epithelial ovarian cancer (EOC); however, its functions in EOC are not fully understood. In this study, we knocked down GDF15 in EOC cells before performing high-throughput sequencing to identify genes regulated by GDF15. GDF15 was overexpressed to determine its effect on the viability, migration, and response of EOC cells to gemcitabine, carboplatin, and paclitaxel. Reprogramming of glucose and cholesterol metabolism in EOC cells was evaluated based on oxygen consumption, lactic acid production, complex I activity, and free and esterified cholesterol levels. The activities of ATP-binding cassette (ABC)B1 and ABCC1 were assessed based on the expulsion efficiency of rhodamine 12. GDF15 overexpression promoted cell viability, migration, and resistance to gemcitabine. In addition, GDF15 induced glycolysis and increased cholesterol levels in EOC cells. Cholesterol metabolism regulated by GDF15 contributed to the resistance of EOC cells to gemcitabine by elevating ABCB1 and ABCC1 levels in lipid rafts. DHCR24 plays an important role in cholesterol synthesis. DHCR24 was identified as a downstream effector of GDF15, because knockdown of DHCR24, but not treatment with statins, suppressed the cancer-promoting effect of GDF15. Overall, GDF15 promoted the resistance of EOC cells to gemcitabine via DHCR24-mediated cholesterol metabolism to elevate ABCB1 and ABCC1 levels in lipid rafts. Therefore, GDF15 and DHCR24 are potential therapeutic targets for suppressing the growth of EOC cells and improving their sensitivity to gemcitabine.