THE EFFECT OF LYCOPENE ON IGF-1 ACTIVITY AND SECRETION IN PRIMARY CULTURES OF PRO

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DESCRIPTION (provided by applicant): Increased insulin-like growth factor (IGF-1) signaling contributes to prostate cancer (PCa) development, growth and metastasis, making IGF-1 a target for both PCa prevention and treatment strategies. Lycopene, a dietary carotenoid found chiefly in tomatoes, has been associated with both a decreased risk and slower progression of PCa. Epidemiological, animal and in vitro studies have suggested inhibition of the IGF-1 axis by lycopene, but the studies have been limited and the results inconsistent. Moreover, the previous human studies were based on serum levels of IGF-1, which may not accurately reflect IGF-1 activity in the prostate. In the prostate, the stromal compartment secretes IGF-1, which interacts with receptors on nearby stromal, epithelial and vascular endothelial cells to stimulate proliferation. Our overall hypothesis is that the anti-cancer activity of lycopene in the prostate is in part due to inhibition of the IGF-1 pathway. Moreover, we postulate there are direct inhibitory effects of lycopene on IGF-1 in normal prostatic epithelial and stromal cells and that these effects will be stronger in PCa-derived cells because they may be more dependent on IGF-1. In this R03 application we will specifically test the following two hypotheses: 1. Lycopene inhibits the IGF-1-induced endpoints of a) cell proliferation, b) intracellular signaling, and/or c) growth factor secretion in normal prostate epithelial and stromal cells. 2. Within the same patient, epithelial cells derived from malignant prostate tissue are more sensitive to the inhibitory effect of lycopene on IGF-1 than cells derived from normal tissue. To test these hypotheses the effects of IGF-1 and lycopene will be examined, both independently and in combination, on cell proliferation, intracellular signaling and growth factor secretion in primary human prostatic cell cultures. The use of primary prostatic cell cultures provides a relevant and complete model to identify prostate-specific changes in IGF-1 pathways because it allows for the separate analysis of epithelial and stromal cells derived from normal and malignant tissue, provides a model for early stage PCa and includes inter-individual variations that established cell lines cannot offer. Once we have determined lycopene's effect on the IGF-1-induced actions in normal prostatic cells, this effect will be compared to those on cells derived from adenocarcinoma.