Carcinogenesis Advance Access published online on June 15, 2005
Carcinogenesis, doi:10.1093/carcin/bgi155
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1 Department of Molecular and Cell Biology and The Cancer Research Laboratory, The University of California at Berkeley, Berkeley, CA 94720
* To whom correspondence should be addressed. Indole-3-carbinol (I3C), a naturally occurring compound found in vegetables of the Brassica genus, such as broccoli and cabbage, is a promising anticancer agent previously shown to induce a G1 cell cycle arrest in human LNCaP prostate cancer cells through regulation of specific G1-acting cell cycle components. Because the androgen receptor (AR) mediates proliferation and differentiation in the prostate and is expressed in nearly all human prostate cancers, the effects of I3C on AR expression and function were examined in LNCaP cells. Immunoblot and quantitative RT-PCR assays revealed that I3C inhibited the expression of AR protein and mRNA levels within 12 hours of indole treatment. I3C down-regulated the reporter activity of LNCaP cells transiently transfected with an AR promoter-luciferase plasmid, demonstrating that a unique response to I3C is the inhibition of AR promoter activity. In contrast to I3C, the natural I3C dimerization product 3,3'-diindolylmethane (DIM), which acts as an androgen antagonist, had no effect on AR expression. To determine the functional significance of the I3C-inhibited expression of AR, the AR-regulated prostate specific antigen (PSA) was utilized as a downstream indicator. I3C down-regulated the expression of PSA transcripts and protein levels, and inhibited PSA promoter activity, as well as that of a minimal androgen responsive element (ARE) containing reporter plasmid. Expression of exogenous AR prevented the I3C disruption of androgen induced PSA expression. Taken together, our results demonstrate that I3C represses AR expression and responsiveness in LNCaP prostate cancer cells as part of its anti-proliferative mechanism.
Received March 24, 2005
Revised May 20, 2005
Accepted June 7, 2005
CANCER BIOLOGY
Indole-3-carbinol inhibition of androgen receptor expression and down-regulation of androgen responsiveness in human prostate cancer cells
2 Department of Nutritional Sciences and Toxicology, The University of California at Berkeley, Berkeley, CA 94720
Gary L. Firestone, E-mail: glfire{at}berkeley.edu
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