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
Related in: MedlinePlus
Mentions: To further elucidate the influence of AGR2 on HIF-1α, we used western blot assays to detect the expression level of HIF-1α in both MCF-7 AGR2-knockdown and MDA-MB-231 AGR2-overexpression cell lines under hypoxic conditions (Fig.3a,b). The results exhibited a stronger HIF-1α upregulation by hypoxia in MDA-MB-231/AGR2 cells, compared with MDA-MB-231/PC cells. By contrast, HIF-1α upregulation was partially blocked in shAGR2 MCF-7 cells, compared with shControl cells. Furthermore, addition of doxorubicin inhibited both hypoxia-induced HIF-1α and AGR2 upregulation. These results suggest that AGR2 is necessary for the full upregulation of HIF-1α by CoCl2.
Affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.