A Role of Novel Serpin Maspinin Prostate Tumor/Bone Interaction

Wayne State University, Detroit MI

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Abstract

DESCRIPTION (provided by applicant): Prostate cancer, the most commonly diagnosed malignancy and the second leading cause of cancer mortality in American men, has a particularly high propensity to metastasize to bone. Unfortunately, PC bone metastasis has no cure. Our long-term goal is to investigate the therapeutic potential of maspin in treating PC bone metastasis. Maspin is a novel epithelial-specific serine protease inhibitor (serpin). Clinical studies indicate that maspin expression is down regulated in invasive and metastatic carcinomas. Experimental evidence from our laboratory and others demonstrates a tumor suppressive role of maspin at the steps of tumor invasion and metastasis. In particular, we have shown that maspin inhibits PC bone tumor growth, PC-induced osteolysis, and PC bone tumor angiogenesis. To explore the therapeutic potential of maspin, we need to have a better understanding of its underlying molecular mechanism. We have shown that maspin dramatically reduces the presentation as well as the activity of PC cell surface-associated urokinase-type plasminogen activator (uPA) and uPA receptor (uPAR). uPA and its zymogen pro-uPA can both bind to uPAR to regulate extracellular proteolysis, cell adhesion and signal transduction. Interestingly, maspin exhibits a novel affinity for pro-uPA. Our preliminary evidence suggests that maspin may trigger receptor-mediated endocytosis of the pro-uPA/uPAR complex before pro-uPA becomes activated. We also showed that maspin specifically binds to type I collagen, the most abundant protein in bone matrix. While maspin stabilized PC cell attachment to type I collagen, type I collagen further enhanced the maspin-mediated pro-uPA endocytosis. Since uPA promotes both osteoblastic and osteolytic tumor bone metastasis, our data collectively support a novel hypothesis: Extracellular maspin may block PC/bone interaction by quenching the cell surface-associated pro-uPA/uPAR complex. Furthermore, the maspin effect on PC/bone interaction is directly regulated by type I collagen. To address this new hypothesis, we will focus on three specific aims. Specific Aim 1 is to investigate the regulation of pro-uPA by maspin. Specific Aim 2 is to investigate the maspin/Col I Interaction. Specific Aim 3 is to investigate the regulation of uPA/uPAR by maspin in PC/bone interaction. Despite the consensus that uPA and uPAR are potential therapeutic targets in PC metastasis, there is no uPA- or uPAR-targeting drug for cancer treatments. To this end, results from this study may provide novel insights regarding how maspin may block the uPA/uPAR complex in the vicious cycle of PC/bone interaction. We will characterize rational maspin mutants in clinically relevant models for PC/bone metastasis to delineate the functional determinants of maspin. The expected results are likely to shed new lights on how to improve the therapeutic intervention of PC bone metastasis.