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

• Published in: Cancer science 2015-08, Vol.106 (8), p.1041-1049
• Main Authors: Li, Zheqi, Zhu, Qi, Hu, Lingyun, Chen, Hao, Wu, Zhenghua, Li, Dawei
• Format: Article
• Language: English
• Subjects: Binding sites; Breast cancer; Cancer therapies; Chemoresistance; Chemotherapy; Doxorubicin; Drug resistance; Endoplasmic reticulum; Gene expression; Hypoxia; MDR1 protein; Molecular modelling; Multidrug resistance; P-Glycoprotein; Proteasomes; Proteins; Therapeutic applications; Transcription
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.12714

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