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

ABSTRACT: 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-2? 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-1? and especially HIF-2?, 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-2?, but not that of HIF-1?. Knockdown of HIF-2? expression substantially attenuated the resistance of OVCAR-3 S and CAOV-3 S cells to ADR, and the HIF-2? overexpression had the opposite effect. Furthermore, in mouse models xenografted with OCSCs, HIF-2? depletion significantly inhibited tumor growth and sensitized OCSCs to ADR in vivo. Mechanistically, HIF-2? 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-2? overexpression endows OCSCs with resistance to ADR by promoting BCRP expression and ADR transportation. Therefore, targeting the HIF-2?/BCRP axis holds therapeutic potential for treating drug-resistant ovarian cancer.

SUBMITTER: He M 

PROVIDER: S-EPMC6360369 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature