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Curcumin inhibits hypoxia-inducible factor-1 by degrading aryl hydrocarbon receptor nuclear translocator: a mechanism of tumor growth inhibition

Cited 142 time in Web of Science Cited 171 time in Scopus
Authors
Choi, Hyunsung; Chun, Yang-Sook; Kim, Seung-Won; Kim, Myung-Suk; Park, Jong-Wan
Issue Date
2006-08-02
Publisher
American Society for Pharmacology and Experimental Therapeutics (ASPET)
Citation
Mol Pharmacol. 2006 Nov;70(5):1664-71. Epub 2006 Jul 31.
Keywords
AnimalsAntineoplastic Agents, Phytogenic/*pharmacologyAryl Hydrocarbon Receptor Nuclear Translocator/genetics/*metabolismCell Division/drug effectsCell Hypoxia/drug effectsCurcumin/*pharmacology/*therapeutic useDown-Regulation/drug effectsGene Expression Regulation, Neoplastic/drug effectsHumansHypoxia-Inducible Factor 1/*antagonists & inhibitors/metabolismMaleMiceMice, NudeNeoplasms/drug therapy/*pathologyOxidation-Reduction/drug effectsOxidative Stress/drug effectsProteasome Endopeptidase Complex/metabolismProtein Processing, Post-Translational/*drug effectsProtein Subunits/metabolismRNA, Messenger/genetics/metabolismTranscription, Genetic/drug effectsTumor Cells, CulturedUbiquitin/metabolism
Abstract
Hypoxia-inducible factor-1 (HIF-1), a transcription factor composed of HIF-1alpha and aryl hydrocarbon receptor nuclear translocator (ARNT), plays a key role in cell survival and angiogenesis in hypoxic tumors, and many efforts have been made to develop anticancer agents that target HIF-1alpha. However, although ARNT is also required for HIF-1 activity, ARNT has been disregarded as a therapeutic target. Curcumin is a commonly used spice and coloring agent with a variety of beneficial biological effects, which include tumor inhibition. In the present study, we tested the possibility that curcumin inhibits tumor growth by targeting HIF-1. The effects of curcumin on HIF-1 activity and expression were examined in cancer cell lines and in xenografted tumors. We found that curcumin inhibits HIF-1 activity and that this in turn down-regulates genes targeted by HIF-1. Moreover, of the two HIF-1 subunits, only ARNT was found to be destabilized by curcumin in several cancer cell types, and furthermore, ARNT expression rescued HIF-1 repression by curcumin. We also found that curcumin stimulated the proteasomal degradation of ARNT via oxidation and ubiquitination processes. In mice bearing Hep3B hepatoma, curcumin retarded tumor growth and suppressed ARNT, erythropoietin, and vascular endothelial growth factor in tumors. These results suggest that the anticancer activity of curcumin is attributable to HIF-1 inactivation by ARNT degradation.
ISSN
0026-895X (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16880289

http://hdl.handle.net/10371/29608
DOI
https://doi.org/10.1124/mol.106.025817
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Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Dept. of Physiology (생리학교실)Journal Papers (저널논문_생리학교실)
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