The 1999 National Cancer Institute Prostate Cancer Progress Review Group Report stated clearly that ?understanding the biology of prostate cancer? is a ?national priority? in battling this cancer which kills approximately 32,000 men annually. In our preliminary data, we demonstrate that we have completed Specific Aims 1-3 and identified that protease activated receptor 1 (PAR1, thrombin receptor) expression is upregulated in prostate cancer as compared to normal prostate epithelial tissue and is poised to play a central role in prostate cancer tumorigenesis and metastasis. Specifically, we demonstrate: A) The development of bone-derived and dura-derived prostate cancer cell (PC) lines as tools to investigate this hypothesis. B) cDNA microarray analysis of normal prostate versus prostate cancer primary tumors, metastatic tumors, and prostate cancer cell lines reveals that PAR1 is overexpressed in prostate cancer, especially those cell lines derived from bone metastases. C) Confirmation of this overexpression by rt-PCR, Northern, and Western analyses. D) Activation of PAR1 increases prostate cancer cell motility. E) Activation of PAR1 increases prostate cancer cell invasion. Our hypothesis, therefore, is that PAR1 activation increases metastasis of prostate cancer cells. To investigate our hypothesis, we have developed the following Specific Aims:
Specific Aim 1 : Investigate the mechanism by which PAR1 activation stimulates prostate cancer cell motility.
Specific Aim 1 A: Investigate the intracellular G-protein pathways involved in PAR1-stimulated motility.
Specific Aim 2 : Investigate the mechanism by which PAR1 activation stimulates prostate cancer cell invasion.
Specific Aim 2 A: Investigate the intracellular G-protein pathways involved in PAR1 stimulated invasion. We believe that these experiments will prove that PAR1 activation plays a critical role in prostate cancer metastasis. Furthermore, these experiments will begin to delineate the mechanism of action of this role, both functionally as well as the intracellular pathways that may be involved. Ultimately, PAR1 may prove to be a target for prostate cancer metastasis prevention and treatment.
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