Anterior gradient 2 is a binding stabilizer of hypoxia inducible factor-1α that enhances CoCl2 -induced doxorubicin resistance in breast cancer cells.
Bottom Line: Our results show that knockdown of AGR2 in MCF-7 cells leads to the suppression of HIF-1α-induced doxorubicin resistance, whereas elevated levels of AGR2 in MDA-MB-231 cells enhance HIF-1α-induced doxorubicin resistance.By specific binding to HIF-1α, the increased level of intracellular AGR2 stabilizes HIF-1α and delays its proteasomal degradation.Finally, we found that AGR2-stabilized HIF-1α 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-1α, acquires wild-type MDR1 overexpression.
Affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.Show MeSH
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Mentions: Previous researches have uncovered that hypoxia increases HIF-1α levels by delaying rapid proteasomal degradation of HIF-1α. In the present study, proteasome inhibitor MG-132 was used to treat MCF-7 and MDA-MB-231 cells with or without CoCl2, to investigate whether AGR2 enhances CoCl2-induced HIF-1α upregulation by interfering with HIF-1α proteasomal degradation (Fig.4a,b). Western blot analysis confirmed that the higher AGR2 levels resulted in the stronger HIF-1α upregulation under CoCl2 treatment in both cell lines. However, combined treatment with MG-132 and CoCl2 caused an equivalent level of HIF-1α upregulation independent of AGR2 levels, which implicates that AGR2 stabilizes CoCl2-induced HIF-1α by affecting the proteasomal degradation process.
Affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.