Miao He1,2, Huizhe Wu1,2, Qian Jiang1,2, Yinuo Liu1,2, Li Han1,2, Yuanyuan Yan1,2, Binbin Wei1,2, Fangxiao Liu1,2, Xiaolan Deng1,2, Huiying Chen1,2, Lin Zhao1,2, Min Wang3, Xin Wu4, Weifan Yao1,2, Haishan Zhao1,2, Jianjun Chen5, Minjie Wei1,2
1Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
2Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Shenyang, China
3Department of gynaecology, Shengjing Hospital of China Medical University, Shenyang, China
4Department of gynaecology The First Affiliated Hospital of China Medical University Shenyang China
5Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA
Tóm tắt
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.
