Hypoxia-inducible factor-2α 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-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.

• Authors: Miao He, Huizhe Wu, Qian Jiang, Yinuo Liu, Li Han, Yuanyuan Yan, Binbin Wei, Fangxiao Liu, Xiaolan Deng, Huiying Chen, Lin Zhao, Min Wang, Xin Wu, Weifan Yao, Haishan Zhao, Jianjun Chen, Minjie Wei
• Journal: Molecular oncology (Mol Oncol) Vol. 13 Issue 2 Pg. 403-421 (02 2019) ISSN: 1878-0261 [Electronic] United States
• PMID: 30536571 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Antineoplastic Agents
• Basic Helix-Loop-Helix Transcription Factors
• Biomarkers, Tumor
• Hypoxia-Inducible Factor 1, alpha Subunit
• Neoplasm Proteins
• endothelial PAS domain-containing protein 1
• Doxorubicin

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2 (genetics, metabolism)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Base Sequence
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Biomarkers, Tumor (metabolism)
• Cell Hypoxia (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Doxorubicin (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Mice, Inbred BALB C
• Neoplasm Proteins (genetics, metabolism)
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Ovarian Neoplasms (drug therapy, genetics, metabolism, pathology)
• Protein Transport (drug effects)
• Spheroids, Cellular (drug effects, metabolism, pathology)