The overall objectives of the current proposal are directed at understanding the molecular mechanism underlying the hormone insensitivity in advanced prostate cancer by delineating the mechanism of AR activation process. The emergence of hormone-independent prostate cancer curtails the effectiveness of hormonal therapies. One mechanism for prostate cancer cells to circumvent the hormonal therapy is to introduce/select mutant androgen receptors (AR), which eventually turn an antagonist into an agonist as evident both in vivo and in vitro. Other perturbations are leading to hormone-independent AR activation. For example, levels of caveolin, a scaffold protein associated with caveolae signaling microdomains, have been correlated with hormone resistance and metastasis in prostate cancer. We demonstrate in cellular models that modulations in caveolin levels dramatically alter the sensitivity of AR to androgen. Furthermore, a transient and dynamic direct interaction between AR and caveolin in response to androgen stimulation is also demonstrated. Our working hypothesis is that AR activation is potentially regulated by a crosstalk with signal complexes associated with caveolin-containing caveolae. The current proposal is designed to rigorously evaluate the interaction between AR and caveolin-1 at molecular, cellular and physiological levels. The immediate goals are: (1) to define in detail the interaction between AR and caveolin-1 at molecular level; (2) to functionally characterize the interaction between AR and caveolin-1 in androgenic receptor activation; (3) to characterize the physiological role of caveolin overexpression in AR signaling using a prostate carcinoma cell culture model; (4) to characterize the effect of caveolin-1 overexpression on LNCap cell tumorigenicity and metastasis using a nude mouse xenograft model. Fully characterizing the interaction between AR and caveolin can be extrapolated to the understanding of the pathobiology of prostate cancer progression as well as the normal prostate epithelial physiology of AR signaling. The long-term goals are to identify novel targets and mechanisms, which could be useful in future development of rational drug targets.
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