期刊
ONCOTARGET
卷 7, 期 12, 页码 14659-14672出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7406
关键词
Nrf2; hypoxia; drug resistance; antioxidant activity; breast tumor
资金
- Ministry of Science and Technology, Taiwan [NSC 101-2320-B-002-020-MY3, 104-2320-B-002 -062 -MY3]
- NIH [CA125618, CA106520]
- Department of Defense, USA [W81XWH-12-1-0148, W81XWH-14-1-0309, W81XWH-15-1-0486]
Hypoxia leads to reactive oxygen species (ROS) imbalance, which is proposed to associate with drug resistance and oncogenesis. Inhibition of enzymes of antioxidant balancing system in tumor cells was shown to reduce chemoresistance under hypoxia. However, the underlying mechanism remains unknown. The key regulator of antioxidant balancing system is nuclear factor erythroid 2-related factor 2 (NFE2L2, Nrf2). In this study, we showed that hypoxia induced ROS production and increased the Nrf2 activity. Nrf2 activation increased levels of its downstream target antioxidant enzymes, including GCLC and GCLM. The Nrf2-overexpressing also confers chemo-resistant MCF7 cells under normoxia. The in vivo mouse model also demonstrated that the chemical inhibition of Nrf2 can increase cisplatin (CDDP) cytotoxicity. Together, these results showed that Nrf2 serves as a key regulator in chemotherapeutic resistance under hypoxia through ROS-Nrf2-GCLC-GSH pathway. Therefore, targeting Nrf2 can be a potential treatment for hypoxia-induced drug resistance in breast cancer cells.
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