Document Detail


Human carbonyl reductase 1 upregulated by hypoxia renders resistance to apoptosis in hepatocellular carcinoma cells.
MedLine Citation:
PMID:  21056497     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: Human carbonyl reductase1 (CBR1) has been reported to protect cells against lipid peroxidation. Since human hepatocellular carcinoma (HCC) cells are under oxidative stress in hypoxic conditions, we tested if CBR1 is upregulated by hypoxia inducible factor (HIF)-1α, helps tumor growth under hypoxia, and renders chemoresistance to cisplatin and doxorubicin in HCC.
METHODS: Luciferase, EMSA, and chromatin immunoprecipitation (ChIP) assays were performed to analyze whether HIF-1α transactivates CBR1 promoter. CBR1 overexpression, siRNA, and inhibitors were used to study the role of CBR1 in tumor survival under hypoxia and chemoresistance to cisplatin and doxorubicin in HCC. FACS and Western blot analysis for oxidative stress markers were performed to measure ROS. Immunohistochemistry (IHC) was performed to analyze CBR1 expression in 78 cases of HCC and 123 cases of colon cancer tissues.
RESULTS: The CBR1 promoter was activated by HIF-1α. CBR1 overexpression enhanced cell survival by decreasing oxidative stress under hypoxia, cisplatin, and doxorubicin treatment. CBR1-siRNA increased apoptosis via increasing oxidative stress. Combinational therapy of CBR1 inhibitors with cisplatin or doxorubicin enhanced cell death in HCC cells. IHC showed CBR1 overexpression in 56 (72%) out of 78 HCC and 88 (72%) out of 123 colon cancer cases.
CONCLUSIONS: Overexpressed CBR1 by HIF-1α plays important roles in tumor growth under hypoxia and chemoresistance to anticancer drugs. The inhibition of CBR1 by specific inhibitors enhances anticancer drug efficacy in HCC. Therefore, we concluded that CBR1 is a good molecular target for the development of anticancer drugs for HCC patients.
Authors:
Eunyoung Tak; Seonmin Lee; Jisun Lee; M A Rashid; Youn Wha Kim; Jae-Hoon Park; Won Sang Park; Kevan M Shokat; Joohun Ha; Sung Soo Kim
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-09-17
Journal Detail:
Title:  Journal of hepatology     Volume:  54     ISSN:  1600-0641     ISO Abbreviation:  J. Hepatol.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-01-18     Completed Date:  2011-04-25     Revised Date:  2012-08-24    
Medline Journal Info:
Nlm Unique ID:  8503886     Medline TA:  J Hepatol     Country:  England    
Other Details:
Languages:  eng     Pagination:  328-39     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Affiliation:
Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
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MeSH Terms
Descriptor/Qualifier:
Alcohol Oxidoreductases / genetics*
Apoptosis / drug effects*
Carcinoma, Hepatocellular / drug therapy*,  enzymology,  pathology
Cell Hypoxia
Cell Line, Tumor
Cisplatin / pharmacology
Colonic Neoplasms / enzymology
Doxorubicin / pharmacology
Drug Resistance, Neoplasm
Gene Expression Regulation, Enzymologic*
Gene Expression Regulation, Neoplastic
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / physiology
Liver Neoplasms / drug therapy*,  enzymology,  pathology
Oxidative Stress
Promoter Regions, Genetic
Up-Regulation
Chemical
Reg. No./Substance:
0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 15663-27-1/Cisplatin; 23214-92-8/Doxorubicin; EC 1.1.-/Alcohol Oxidoreductases; EC 1.1.1.184/CBR1 protein, human

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