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‐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.
Highlights
Ovarian cancer is the most lethal gynecological malignancy and one of the leading causes of cancer-related mortality in women in the USA, resulting in an estimated 22 440 new cases and 14 080 deaths in 2017 according to the American Cancer Society (Siegel et al, 2017)
Transwell invasion assays showed that the number of OVCAR-3 S and CAOV-3 S cells that invaded into the lower transwell chamber was significantly greater than the number parental cells that were able to invade (Fig. S1C)
We found that OVCAR-3 S and CAOV-3 S cells re-differentiated into their parental OVCAR-3 and CAOV-3 cells in DMEM culture medium supplemented with 10% FBS for 72 h (Fig. S1D) by referring to Ponti et al.’s (2005) and Wu et al.’s (2010) reports
Summary
Ovarian cancer is the most lethal gynecological malignancy and one of the leading causes of cancer-related mortality in women in the USA, resulting in an estimated 22 440 new cases and 14 080 deaths in 2017 according to the American Cancer Society (Siegel et al, 2017). It is increasingly evident that heterogeneous ovarian cancers contain a subpopulation of cancer stem cells (CSCs) with enhanced self-renewal, differentiation, and chemoresistance capabilities (Jung et al, 2016). These ovarian CSCs (OCSCs), with their increased chemoresistance, are believed to contribute to tumor maintenance and recurrence; targeting OCSCs may provide a more effective novel therapeutic strategy for ovarian cancer treatment. Accumulating evidence in recent years suggests that HIF-2 plays important roles in the chemoresistance of tumor cells, especially in promoting a more stem-like phenotype in CSCs (Pietras et al, 2009; Zhao et al, 2014). Nothing has yet been reported regarding the regulatory effects and mechanisms of HIF-2a on the drug resistance in OCSCs, which is worthy of further investigation
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