? Lycopene, the red pigment of the tomato, is a dietary carotenoid and a potent antioxidant that has been associated by prospective and retrospective epidemiological studies with a decreased incidence of prostate cancer in men. Our preliminary clinical studies in men with prostate cancer indicate that oral administration of lycopene elevates serum and prostate lycopene levels and reduces serum prostate specific antigen (PSA). Our preliminary cell culture studies using human prostate cancer cells show that lycopene is absorbed selectively by and inhibits the proliferation of the androgen sensitive prostate cancer cell line LNCaP but not the androgen-insensitive prostate cancer cell lines DU145 and PC-3. We propose to expand upon these cell culture studies by measuring and comparing the rates of lycopene uptake by the androgen-sensitive cell lines LNCaP, PZ-HPV-7, and BPH-1 (which represent human prostate cancer, BPH, and normal epithelial cells, respectively), and the androgen-insensitive prostate cancer cell lines DU145, PC-3, C4-2B, and CWR22Rv1. Whether the rates of lycopene uptake are inversely proportional to inhibition of proliferation in these cells will be determined. In order to clarify the mechanism of action of lycopene as an antiproliferative agent, we will measure the sub-cellular distribution of lycopene and then investigate changes in protein expression both globally and on the sub-cellular level using the ICAT quantitative proteomics methodology. In addition, a lycopene affinity column will be prepared and used to screen lycopene sensitive cells for a lycopene receptor or binding protein which will be identified using mass spectrometry-based proteomics. Lycopene binding to the androgen receptor will also be investigated. Based on our observation that lycopene reduces PSA levels in men with prostate cancer, we will investigate how the intracellular expression and secretion of PSA is altered by prostate cells treated with lycopene in culture; in addition, we will determine whether total PSA and percent-free PSA are altered in the serum of healthy men receiving lycopene supplements. Finally, we will determine the bioavailability and half-life of two potentially therapeutic doses of lycopene, 30 mg per day and 60 mg per day, using stable isotope labeled lycopene and HPLC-tandem mass spectrometry. These human studies will provide vital information for the design of future clinical trials investigating the chemoprevention of prostate cancer by lycopene. ? ? ?
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