Prostate cancer (CaP) progresses from a hormone dependent to refractory state. Hormone ablation therapy remains the single most effective treatment for early stage CaP. Unfortunately, most tumors relapse and become androgen-refractory or independent. The prognosis for the latter stage remains poor and no effective treatment is in sight. There is thus, an urgent need for understanding the progression factors that lead to androgen-refractory status, with the hope that some of these factors could be targets for therapy in the future. Considering the heterogeneous nature of CaP, there are likely different progression factors that allow cells to grow without the need for androgen; some may activate an autonomous growth pathway, bypassing the androgen receptor, while others may activate androgen receptors, bypassing androgen. In this proposal, we focus on neurotrophic factors or neuropeptides, which are known to be released by advanced prostate cancers and have been implicated in the development of the androgen-independent state. We have obtained preliminary data demonstrating that these factors can substitute for androgen to stimulate the growth of androgen dependent CaP cells, both in vitro and in vivo. They do so by activating androgen receptor in the absence of androgen and by engaging a signal complex consisting of non-receptor tyrosine kinases FAK, Src and Etk. Tyrosine kinases, while a minor class of protein kinases, represent a major class of oncogenes. The PI's lab has had extensive experience in studying tyrosine kinases. All three kinases described above have been shown to possess oncogemc properties, and Etk was originally co-discovered in the PI's lab from CaP cells. This kinase, by virtue of having a PH, a SH3 and a SH2 domain serves as an active enzyme as well as a scaffold protein. We believe this is the first time that a molecular link between G-protein coupled receptors, to which neurotrophic factors bind, and nuclear receptors, to which androgen binds, was demonstrated. There are two specific aims of this proposal: 1) To characterize the role of tyrosine kinase in neuropeptide signaling and 2) To characterize the role of kinase signaling in androgen receptor activation.
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