Hypoxia-inducible factor-2α directly promotes BCRP expression and mediates the resistance of ovarian cancer stem cells to adriamycin.

Ovarian cancer stem cells (OCSCs) are sources of tumor chemoresistance and recurrence. A hypoxic microenvironment contributes to the chemoresistance of cancer stem cells (CSCs), but the underlying mechanism is not fully understood yet. Here, we show that increased HIF-2α expression is associated with enhanced stemness of OCSCs and poor outcomes in ovarian cancer patients. OVCAR-3 and CAOV-3 sphere-forming (OVCAR-3 S and CAOV-3 S) cells with OCSC-like properties showed strong resistance to adriamycin (ADR). Hypoxia (1% O₂ ) induced high expression of both HIF-1α and especially HIF-2α, and increased the resistance of OVCAR-3 S and CAOV-3 S cells to ADR. Notably, treatment with ADR further increased the expression of HIF-2α, but not that of HIF-1α. Knockdown of HIF-2α expression substantially attenuated the resistance of OVCAR-3 S and CAOV-3 S cells to ADR, and the HIF-2α overexpression had the opposite effect. Furthermore, in mouse models xenografted with OCSCs, HIF-2α depletion significantly inhibited tumor growth and sensitized OCSCs to ADR in vivo. Mechanistically, HIF-2α directly promotes transcription/expression of BCRP, a gene encoding a transporter protein responsible for pumping drugs (e.g., ADR) out of cells, which in turn increases drug resistance due to increased drug transportation. Collectively, our studies reveal a novel drug-resistant mechanism in ovarian cancer by which hypoxia (and ADR treatment)-induced HIF-2α overexpression endows OCSCs with resistance to ADR by promoting BCRP expression and ADR transportation. Therefore, targeting the HIF-2α/BCRP axis holds therapeutic potential for treating drug-resistant ovarian cancer.