Abstract
Hypoxia-inducible factor-1 (HIF-1), a transcription factor composed of HIF-1α 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-1α. 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.
Footnotes
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This work was supported by research funds of Seoul National University College of Medicine (21-2005-014) and Seoul National University Cancer Research Institute (2005).
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H.C. and Y.-S.C. contributed equally to this work.
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ABBREVIATIONS: HIF, hypoxia-inducible factor; ARNT, aryl hydrocarbon receptor nuclear translocator; bHLH, basic helix-loop-helix; PAS, Per-ARNT-Sim; EPO, erythropoietin; VEGF, vascular endothelial growth factor; RT-PCR, reverse-transcription polymerase chain reaction; AMC, 7-amino-4-methylcoumarin; TTBS, Tris-buffered saline/Tween 20; DMSO, dimethyl sulfoxide; NAC, N-acetyl cysteine; BSO, buthionine sulfoximine; β-gal, β-galactoside; HA, hemagglutinin; MG132, N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal; Z-VAD-FMK, Z-Val-Ala-Asp(OMe)-fluoromethyl ketone.
- Received April 16, 2006.
- Accepted July 31, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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