Carcinogenesis Advance Access published online on August 3, 2007
Carcinogenesis, doi:10.1093/carcin/bgm144
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Resveratrol Suppresses Prostate Cancer Progression in Transgenic Mice
1 Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama
2 UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama
3 Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
* To whom requests for reprints should be addressed: Dr. Coral A. Lamartiniere, University of Alabama at Birmingham, Department of Pharmacology and Toxicology, 1670 University Blvd., Volker Hall 124, Birmingham, AL, 35294-0019. Email: Coral{at}uab.edu.
Resveratrol, a natural polyphenolic phytochemical, has been reported to act as an antioxidant and provide anti-cancer 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 (TRAMP) males were fed resveratrol (625 mg resveratrol/kg AIN-76A diet) or phytoestrogen-free, control diet (AIN-76A) starting at five 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 (DLP), resveratrol significantly inhibited cell proliferation, increased androgen receptor (AR), estrogen receptor-ß (ER-ß), and insulin-like growth factor-1 receptor (IGF-1R), and significantly decreased IGF-1, and phospho-extracellular regulating kinase 1 (phospho-ERK 1). In the ventral prostate (VP), resveratrol significantly reduced cell proliferation and phospho-ERKs 1 and 2, but did not significantly alter IGF-1R and IGF-1. Serum total testosterone, free testosterone, estradiol, dihydrotestosterone (DHT), and sex hormone binding globulin (SHBG) concentrations and SV-40 Tag 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 three weeks with 625 mg resveratrol/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, ER-ß, provide a biochemical basis for resveratrol suppressing prostate cancer development.
Key Words: Prostate Cancer • Chemoprevention • Resveratrol • TRAMP • IGF-1
Received October 25, 2006; revised June 11, 2007; accepted June 11, 2007.
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