TEL: +86 571 56623320    EMAIL: [email protected]

Anterior Gradient 2 Is a Binding Stabilizer of Hypoxia Inducible Factor-1α That Enhances Cocl2 -Induced Doxorubicin Resistance in Breast Cancer Cells
SUNLONG BIOTECH / 2024-01-09
  • Author:Li, Z., Zhu, Q., Hu, L., Chen, H., Wu, Z. & Li, D.

  • Periodical:Cancer science 106, 1041-1049 (2015)

  • Article source

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 (AGR2), 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 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. AGR2 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 AGR2 promoter sequence. 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. 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.

User Comment(Total0User Comment Num)

  • No comment
Total 0 records, divided into1 pages First Prev Next Last
Username: Anonymous user
E-mail:
Rank:
Content:
Verification code: captcha

Call us

+86 571 56623320

Address

Room 1-315, Kongle Changqing Building, No. 160 Guangye Road,Gongshu District, Hangzhou City, Zhejiang Province, China

Join Us with

Leave a message
* To protect against spam, please pass the CAPTCHA test below.