Role of Thromboxane in Prostate Cancer Progression

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DESCRIPTION (provided by applicant): Thromboxane (TX) synthase metabolizes the cyclooxygenase product, prostanglandin HZ, into thromboxane A2 (TXA.2), which can cause vessel constriction, platelet activation, and aggregation. We have demonstrated that TX synthase expression is stimulated during prostate cancer progression and that this enzyme is involved in controlling tumor cell motility. We hypothesize that the stimulation of TX synthase expression is an integral part of prostate carcinogenesis and TX synthase confers upon prostate cancer cells with increased motility and invasiveness, and also with increased capability to elaborate host tissues such as the hemostatic system, especially platelets, to facilitate tumor progression and metastasis. The three specific aims present a road map to define when and how TX synthase is stimulated during prostate cancer initiation and progression, what role TX synthase and TXA2 play, and whether or not the hemostatic system is impeded to facilitate prostate tumor progression and metastasis through thrombane signaling loop. In the first specific aim, we will define the pattern of TX synthase expression during prostate cancer initiation and progression using TRAMP mouse model for prostate cancer. In the specific aim 2, we will characterize TXA.2 receptors expressed in prostate cancer cells and further study the signaling pathway involved for TXA2 to control cytoskeleton and motility. In the third specific aim, we will over express or knock out TX synthase expression in tumor cells and examine the resultant changes in cell phenotypes in vitro, interaction with platelets, and tumor formation, progression, and metastasis in vivo. We believe the proposed studies will provide significant insights into the process of prostate cancer initiation and progression and also afford us an exciting avenue for intervention previously unexplored.