Carcinogenesis Advance Access originally published online on February 26, 2004
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Carcinogenesis, Vol. 25, No. 7, 1119-1128,
July 2004
Carcinogenesis vol.25 no.7 © Oxford University Press 2004; all rights reserved.
ARTICLE |
Indole-3-carbinol stimulates transcription of the interferon gamma receptor 1 gene and augments interferon responsiveness in human breast cancer cells
1 Department of Molecular and Cell Biology and The Cancer Research Laboratory, 2 Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley, CA 94720-3200, USA, 3 Incyte Genomics, Palo Alto, California, USA and 4 Laboratory of Molecular Biology, Medical Research Center, Kochi Medical School, Okoh, Nankoku, Kochi 783-8505, Japan
5 Present address: Agilent Technologies Inc., 3500 Deer Creek, Palo Alto, CA 94304, USA
6 To whom correspondence should be addressed Email: glfire{at}uclink4.berkeley.edu
Indole-3-carbinol (I3C), a naturally occurring compound of Brassica vegetables, has promising anticancer properties and activates an anti-proliferative pathway that induces a G1 cell cycle arrest of human breast cancer cells. A microarray analysis of I3C treated versus untreated MCF-7 breast cancer cells revealed that I3C increased expression of the interferon gamma receptor 1 (IFN
R1). Western blot and RT–PCR analysis demonstrated that I3C strongly and rapidly stimulated IFNR1 gene expression. Transfection of a series of 5' deletion constructs of the IFNR1 reporter plasmids revealed that I3C significantly stimulates the promoter activity of the IFNR1 and uncovered an I3C-responsive region between –540 and –240 bp of the IFNR1 promoter. I3C stimulation of the IFNR1 expression suggests that indole treatment should enhance IFN responsiveness in breast cancer cells. A combination of I3C and IFN synergistically activated STAT1 proteins by increasing phosphorylation at the Tyr-701 site. In addition, I3C and IFN together more effectively induced a G1 cell cycle arrest and stimulated expression of the p21Waf1/Cip1 cell cycle inhibitor, compared with the effects of either agent alone. Our results suggest that one mechanism by which I3C mediates these anticancer effects is by stimulating expression of the IFNR1 and augmenting the IFN response in MCF-7 human breast cancer cells.
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