Anterior gradient 2 is a binding stabilizer of hypoxia inducible factor-1 that enhances CoCl2-induced doxorubicin resistance in breast cancer cells

作者：Li, Zheqi; Zhu, Qi; Hu, Lingyun; Chen, Hao; Wu, Zhenghua; Li, Dawei^*

来源：CANCER SCIENCE, 2015, 106(8): 1041-1049.

DOI：10.1111/cas.12714

• Anterior gradient 2
• chemical hypoxia
• doxorubicin resistance
• hypoxia inducible factor-1
• hypoxia responsive element

Hypoxia inducible factor-1 (HIF-1) is associated with human breast cancer chemoresistance. Various reports have suggested that multiple pathways are involved in HIF-1 induction and that the molecular mechanisms regulating HIF-1-induced chemoresistance are still not fully understood. Here, we report that anterior gradient 2 (AGR2), a proposed breast cancer biomarker, is an essential regulator in hypoxia-induced doxorubicin resistance through the binding and stabilization of HIF-1. Our results show that knockdown of AGR2 in MCF-7 cells leads to the suppression of HIF-1-induced doxorubicin resistance, whereas elevated levels of AGR2 in MDA-MB-231 cells enhance HIF-1-induced doxorubicin resistance. AGR2 expression, in turn, is upregulated by the hypoxic induction of HIF-1 at both translational and transcriptional levels via a hypoxia-responsive region from -937 to -912bp on the AGR2 promoter sequence. By specific binding to HIF-1, the increased level of intracellular AGR2 stabilizes HIF-1 and delays its proteasomal degradation. Finally, we found that AGR2-stabilized HIF-1 escalates multiple drug resistance protein 1 (MDR1) mRNA levels and limits doxorubicin intake of MCF-7 cells, whereas MCF-7/ADR, a doxorubicin resistant cell line with deficient AGR2 and HIF-1, acquires wild-type MDR1 overexpression. Our findings, for the first time, describe AGR2 as an important regulator in chemical hypoxia-induced doxorubicin resistance in breast cancer cells, providing a possible explanation for the variable levels of chemoresistance in breast cancers and further validating AGR2 as a potential anti-breast cancer therapeutic target.

• 出版日期2015-8
• 单位上海交通大学