Anterior gradient 2 is a binding stabilizer of hypoxia inducible factor-1α that enhances CoCl2 -induced doxorubicin resistance in breast cancer cells.
Anterior gradient 2 is a binding stabilizer of hypoxia inducible factor-1α that enhances CoCl2 -induced doxorubicin resistance in breast cancer cells.
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Anterior Gradient 2 是缺氧诱导因子 1 的结合稳定剂，可增强乳腺癌细胞中 CoCl2 诱导的阿霉素耐药性
DOI：
10.1111/cas.12714
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发表时间：
2015-08
期刊：
影响因子：
5.7
通讯作者：
Li D
中科院分区：
文献类型：
--
作者：
Li Z;Zhu Q;Hu L;Chen H;Wu Z;Li D
缺氧诱导因子-1 α（HIF-1α）与乳腺癌化疗耐药相关。各种报道表明，多种途径参与HIF-1α诱导，并且调节HIF-1α诱导的化疗耐药性的分子机制仍不完全清楚。在这里，我们报告了前梯度2（AGR 2），一个拟议的乳腺癌生物标志物，是一个重要的调节器，在缺氧诱导的阿霉素耐药通过结合和稳定的HIF-1α。我们的研究结果表明，MCF-7细胞中AGR 2的敲低导致HIF-1α诱导的多柔比星耐药性的抑制，而MDA-MB-231细胞中AGR 2水平的升高增强HIF-1α诱导的多柔比星耐药性。HIF-1α通过AGR 2启动子序列上的-937至-912 bp的低氧反应区在翻译和转录水平上调AGR 2的表达。通过与HIF-1α特异性结合，细胞内AGR 2水平的增加稳定了HIF-1α并延迟了其蛋白酶体降解。最后，我们发现，AGR 2稳定的HIF-1α使MCF-7细胞的多药耐药蛋白1（MDR 1）mRNA水平升高，并限制了MCF-7细胞对阿霉素的摄入，而MCF-7/ADR，一种AGR 2和HIF-1α缺陷的阿霉素耐药细胞系，获得了野生型MDR 1过表达。我们的研究结果首次将AGR 2描述为乳腺癌细胞中化学缺氧诱导的阿霉素耐药性的重要调节因子，为乳腺癌中化学耐药性的可变水平提供了可能的解释，并进一步验证AGR 2作为潜在的抗乳腺癌治疗靶点。
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.