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Carcinogenesis Advance Access originally published online on August 3, 2007
Carcinogenesis 2007 28(9):1946-1953; doi:10.1093/carcin/bgm144
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Resveratrol suppresses prostate cancer progression in transgenic mice

Curt E. Harper1, Brijesh B. Patel1, Jun Wang1, Alireza Arabshahi1, Isam A. Eltoum2,3 and Coral A. Lamartiniere1,2,*

1 Department of Pharmacology and Toxicology
2 UAB Comprehensive Cancer Center
3 Department of Pathology, University of Alabama at Birmingham, 1670 University Boulevard, Birmingham, AL 35294-0019, USA

* To whom correspondence should be addressed. Tel: 205-934-7139; Fax: 205-934-8240; Email: coral{at}uab.edu

Resveratrol, a natural polyphenolic phytochemical, has been reported to act as an antioxidant and provide anticancer activities. We hypothesized that resveratrol would exert a chemopreventive effect against prostate cancer via regulation of sex steroid receptor and growth factor signaling pathways. In the current study, Transgenic Adenocarcinoma Mouse Prostate males were fed resveratrol (625 mg resveratrol per kg AIN-76A diet) or phytoestrogen-free, control diet (AIN-76A) starting at 5 weeks of age. Mechanisms of action and histopathology studies were conducted at 12 and 28 weeks of age, respectively. Resveratrol in the diet significantly reduced the incidence of poorly differentiated prostatic adenocarcinoma by 7.7-fold. In the dorsolateral prostate, resveratrol significantly inhibited cell proliferation, increased androgen receptor, estrogen receptor-ß, and insulin-like growth factor-1 receptor, and significantly decreased insulin-like growth factor (IGF)-1 and phospho-extracellular regulating kinase 1 (phospho-ERK 1). In the ventral prostate, resveratrol significantly reduced cell proliferation and phospho-ERKs 1 and 2, but did not significantly alter insulin-like growth factor-1 receptor and IGF-1. Serum total testosterone, free testosterone, estradiol, dihydrotestosterone and sex hormone-binding globulin (SHBG) concentrations and Simian Virus-40 large T antigen expression in the prostate were not altered in resveratrol-treated mice. Total resveratrol concentration in the blood serum of 12-week-old mice treated for 3 weeks with 625 mg resveratrol per kg diet was 52 ± 18 nM. The decrease in cell proliferation and the potent growth factor, IGF-1, the down-regulation of downstream effectors, phospho-ERKs 1 and 2 and the increase in the putative tumor suppressor, estrogen receptor-ß, provide a biochemical basis for resveratrol suppressing prostate cancer development.

Abbreviations: AR, androgen receptor; BSA, bovine serum albumin; DHT, dihydrotestosterone; DLP, dorsolateral prostate; ELISA, enzyme-linked immunosorbent assay; ERK, extracellular regulating kinase; ER-{alpha}, estrogen receptor-{alpha}; ER-ß, estrogen receptor-ß; IGF, insulin-like growth factor; IGF-BP3, insulin-like growth factor-binding protein 3; IGF-1R, insulin-like growth factor-1 receptor; PBS, phosphate-buffered saline; phospho-ERK 1, phospho-extracellular regulating kinase 1; PIN, prostatic intraepithelial neoplasia; SV-40 Tag, Simian Virus-40 large T antigen; TRAMP, Transgenic Adenocarcinoma Mouse Prostate; VP, ventral prostate

Received October 25, 2006; revised June 11, 2007; accepted June 11, 2007.


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