PROJECT SUMMARY Prostate cancer (PCa) is the most common cancer among men. Although androgen deprivation has been a major therapy for advance PCa patients, it inevitably becomes ineffective once the cancer transforms to hormone resistant. In order to design better therapeutic strategies, intensive research effort has focused on the identification of novel molecular targets. It is known that the enhanced activation of the mitogen-activated protein kinase (MAPK) Raf-MEK-ERK pathway is correlated with the progression, androgen independence and poor prognosis of PCa and thus, the signaling molecules involved in the regulation of this pathway have been thought to be suitable targets for therapeutic intervention. However, the molecular mechanisms underlying the hyper-activation of Raf-MEK-ERK pathway in PCa remain poorly defined. Despite the fact that multiple genetic mutations have been identified in receptor tyrosine kinases, Ras, Raf and MEK which largely contribute to the elevated activation of the MAPK pathway in many types of malignancies, these mutations are infrequent in PCa patients. The goal of this application is to reveal oncogenic actions of ADP-ribosylation factor 1 (ARF1) via activating the MAPK pathway in PCa cells and explore ARF1-mediated signaling as a novel therapeutic target for prostate tumorigenesis. Our preliminary studies have demonstrated for the first time that ARF1 is a potent oncogene which significantly contributes to the elevated activation of the MAPK pathway and the progression of PCa. The central hypothesis of this proposal is that ARF1-mediated Golgi-associated activation of the MAPK pathway plays a crucial role in prostate tumorigenesis and targeting it will prevent PCa progression. There are three Specific Aims in the proposal. Specific Aim 1 will test the hypothesis that oncogenic G protein-coupled receptors activate ARF1 via the translocation of G?? subunits to the Golgi in PCa cells. Specific Aim 2 will test the hypothesis that the Golgi apparatus spatially provides a platform upon which ARF1 activates the MAPK pathway via a direct interaction with Raf1 in PCa cells. Specific Aim 3 will test the hypothesis that ARF1 inhibitors effectively suppress prostate cancer progression. Overall, this project will reveal previously unrecognized functions of ARF1 in PCa biology and explore a novel means to inhibit the tumorigenesis of PCa by targeting ARF1-mediated Golgi-associated oncogenic signaling. These studies will directly impact the future development of effective therapy for PCa patients.
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