期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 60, 期 -, 页码 201-210出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2013.02.022
关键词
Mad1; Mitochondria; ROS; Doxorubicin; Colon cancer; Free radicals
资金
- Healthcare Technology RD grant [A091081]
- Korea Ministry for Health, Welfare Family Affairs
- National Research Foundation [2009-0090188, 2010-0029948]
- Korea Ministry of Education, Science Technology
- National Research Foundation of Korea [2009-0090188, 2010-0029948] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Cancer cells acquire resistance to chemotherapy under hypoxia, which is mainly driven by the transcription factor HIF (hypoxia-inducible factor). Yet, it is uncertain which molecules mediate such resistance. While profiling gene expression in colon cancer cells, we found that Mad1 (MAX dimerization protein 1) is substantially induced during hypoxia. The hypoxic induction of Mad1 was confirmed by RTPCR and Western blotting. The Mad1 expression was attenuated by HIF-1 alpha small interfering (si) RNAs, but less so by HIF-2 alpha siRNAs. Moreover, luciferase reporter and chromatin immunoprecipitation analyses revealed that HIF-1 transactivates the MAD1 gene by directly targeting a putative hypoxia-response element in the MAD1 promoter. We next investigated if Mad1 is responsible for the hypoxia-induced drug resistance. We treated colon cancer cells with doxorubicin and found that the cells under hypoxia survived more than those under normoxia. The doxorubicin resistance was not induced in Mad1-knocked-down cells even under hypoxia. Mad1 knockdown reactivated the caspase-9/caspase-3/PARP apoptotic pathway under hypoxia. Moreover, doxorubicin-induced production of reactive oxygen species was significantly reduced under hypoxia, which was reversed by Mad1 knockdown. During hypoxia, mitochondria became bigger in size and less active in respiration, both of which were attenuated by Mad1 knockdown. These data indicate that hypoxia-induced Math lowers doxorubicin-stimulated generation of reactive oxygen species through mitochondrial inhibition and subsequently contributes to tumor resistance to doxorubicin. Therefore, Mad1 could be a potential target for sensitizing cancer cells to redox-cycling drugs such as doxorubicin. (C) 2013 Elsevier Inc. All rights reserved.
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