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

摘要

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 style="fixed-case">HIF‐2α, but not that of style="fixed-case">HIF‐1α. Knockdown of style="fixed-case">HIF‐2α expression substantially attenuated the resistance of style="fixed-case">OVCAR‐3 S and style="fixed-case">CAOV‐3 S cells to style="fixed-case">ADR, and the style="fixed-case">HIF‐2α overexpression had the opposite effect. Furthermore, in mouse models xenografted with style="fixed-case">OCSCs, style="fixed-case">HIF‐2α depletion significantly inhibited tumor growth and sensitized style="fixed-case">OCSCs to style="fixed-case">ADR in vivo. Mechanistically, style="fixed-case">HIF‐2α directly promotes transcription/expression of style="fixed-case">BCRP, a gene encoding a transporter protein responsible for pumping drugs (e.g., style="fixed-case">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 style="fixed-case">ADR treatment)‐induced style="fixed-case">HIF‐2α overexpression endows style="fixed-case">OCSCs with resistance to style="fixed-case">ADR by promoting style="fixed-case">BCRP expression and style="fixed-case">ADR transportation. Therefore, targeting the style="fixed-case">HIF‐2α/ style="fixed-case">BCRP axis holds therapeutic potential for treating drug‐resistant ovarian cancer.