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Carcinogenesis Advance Access published online on May 16, 2006
Carcinogenesis, doi:10.1093/carcin/bgl075
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received October 19, 2005
Revised April 28, 2006
Accepted May 5, 2006

CARCINOGENESIS

Repression of androgen receptor in prostate cancer cells by phenethyl isothiocyanate

L. G. Wang 1 *, X. M. Liu 1, and J. W. Chiao 2

1 NYU Cancer Institute, NYU School of Medicine, Manhattan VAMC 18th Floor, Rm. 18003 W, 423 East 23rd Street, New York NY 10010
2 Department of Medicine, Vosbargh 207, New York Medical College, Valhalla, NY 10595

* To whom correspondence should be addressed.
L. G. Wang, E-mail: Longgui.Wang{at}med.NYU.edu


  Abstract

Background: Prostate cancer usually progresses to androgen refractory after an initial anti-androgen treatment. The androgen receptor (AR) is a pivotal factor for the androgen-mediated growth and maintenance of the prostate. Abnormality of the AR, such as over-expression has been postulated to be related to the hormone independent growth of the cancer. Although we previously demonstrated that the AR expression could be modulated by isothiocyanates, which are natural constituents of cruciferous vegetables, the mechanism however, remained to be clarified. We have since investigated the mechanism of phenethyl isothiocyanate (PEITC) in AR regulation. Methods: A human androgen dependent prostate cancer cell line LNCaP (AD), and its sub-line LNCaP (AI) that is androgen independent but over-expressing AR, were exposed to PEITC. The effects of PEITC on cell growth, and AR expression/transcription were analyzed with MTT assay, real-time PCR, and Western blotting. The AR promoter activity was analyzed with the reporter activity after transfection with pAR-luc. The effects on Sp1, the major transcription factor of the AR, were tested with Sp1-luc activity, Western blotting, and electrophoretic mobility shift assay (EMSA). Results: PEITC induced a significant growth inhibition, with equal IC50, in both AD and AI cells. The AR present in both cells was repressed as demonstrated with real-time PCR and Western blot. PEITC mediates dual effects at transcriptional and post-translational levels to regulate the AR. At transcriptional level the AR level was reduced via inhibition of the transcription factor Sp1, and at post-translational level by accelerating protein degradation. Conclusion: PEITC represses AR transcription and expression, and mediates growth arrest in androgen dependent and independent prostate cancer cells. With the AR modulation and growth attenuation, PEITC and possibly other isothiocyanates, may prevent and inhibit hormone sensitive and refractory prostate cancer.


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