Carcinogenesis Advance Access originally published online on June 26, 2008
Carcinogenesis 2008 29(10):2001-2010; doi:10.1093/carcin/bgn131
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Differential effects of resveratrol on androgen-responsive LNCaP human prostate cancer cells in vitro and in vivo
Diet, Genomics and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agriculture Research Service, United States Department of Agriculture, 10300 Baltimore Avenue, Building 307C, Room 132, Beltsville, MD 20705, USA
1 Laboratory of Cellular Regulation and Carcinogenesis, National Cancer Institutes, National Institutes of Health, Bethesda, MD 20892, USA
2 Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742, USA
3 Department of Pharmaceutical Sciences and Pharmacology and Toxicology Graduate Program College of Pharmacy, Washington State University, Pullman, WA 99164-6534, USA
4 National Food Research Institute, Tsukuba, Ibaraki 305-8642, Japan
5 Nutritional Sciences Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
6 Biometrical Consulting Service, Beltsville Area, Agriculture Research Service, United States Department of Agriculture, Beltsville, MD 20705, USA
7 Division of Nutritional Sciences, University of Texas at Austin, Austin, TX 78712, USA
8 Department of Carcinogenesis, MD Anderson Cancer Center, Smithville, TX 78957, USA
* To whom correspondence should be addressed. Tel: +1 301 504 8459; Fax: +1 301 504 9456; Email: tom.wang{at}ars.usda.gov
Resveratrol is a phytochemical that has been under consideration for use as a prostate cancer chemopreventive agent. However, the efficacy, as well as the mechanisms of action of resveratrol on prostate cancer prevention, remains largely unknown. This study seeks to address these questions and examine the cancer preventive effects of resveratrol using complementary human LNCaP prostate cancer cell culture and xenograft models. In cultured LNCaP cells, we found that resveratrol inhibited cell growth. The growth inhibitory effects of resveratrol appeared to be through modulation of both androgen- and estrogen-mediated events. Global gene expression analysis using microarrays identified androgen-responsive genes as a group of genes universally affected by resveratrol in LNCaP cells in vitro. The effect of resveratrol on expression of these genes appeared to be through inhibition of both androgen- and estrogen-mediated transcription. In a xenograft model, resveratrol delayed LNCaP tumor growth and inhibited expression of a marker for steroid hormone responses. However, exposure to resveratrol also led to increased angiogenesis and inhibition of apoptosis in the xenograft. In summary, resveratrol may act through modulation of steroid hormone-dependent pathways to inhibit prostate cancer cell growth in both culture and xenografts, but exposure in vivo may be of concern.
Abbreviations: AR, androgen receptor; ARG, androgen-responsive gene; B2M, beta-2-microglobulin; CDKN1A, cyclin-dependent kinase inhibitor 1A/p21WAF1/CIP1; CDS, charcoal–dextran-treated FBS; FBS, fetal bovine serum; FU, fluorescence units; HPLC, high-performance liquid chromatography; IGF-1, insulin-like growth factor-1; IGF-1R, insulin-like growth factor-1 receptor; IHC, immunohistochemical; IS, Internal standard; mRNA, messenger RNA; PBS, phosphate-buffered saline; PCNA, proliferating cell nuclear antigen; PECAM-1, platelet/endothelial cell adhesion molecule-1; PSA, prostate-specific antigen; RT–PCR, reverse transcription–polymerase chain reaction; SEPP1, selenoprotein P, plasma, 1; STK39, serine threonine kinase 39; VEGF, vascular endothelial growth factor
Received October 18, 2007; revised May 29, 2008; accepted May 29, 2008.