This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have discovered a protein, prosaposin (PSAP), that we hypothesize to be a major contributor to the growth and invasion of human PCa cells. PSAP is a 70-kDa protein identified, cloned, and characterized by our laboratory and found to increase growth, migration, and invasion of PCa cells. Previously, we showed that PSAP expression increases upon androgen-independent (AI) progression, with marked overexpression in metastatic human AI PCa cells. Our current data show that down modulating PSAP expression by shRNA leads to a significant reduction of (a) PCa cells adhesion to basement membrane proteins, (b) the expression of the proteolytic enzymes MMP-9 and uPA, and (c) migratory and invasion properties of PCa cells. To test our hypothesis that PSAP contributes substantially to invasion of human PCa cells, we propose the following Specific Aims: 1. Define the mechanisms by which PSAP regulates PCa invasion in vitro. We will use our established stable transfectants of PCa cell lines (PC-3, DU-145, LNCaP) with an increased or a decreased level of PSAP expression to examine the cause and effect relationship between PSAP and PCa cell adhesion to extracellular matrix proteins (e.g., Laminin-1, Matrigel) and down stream signaling pathways in relation to FAK activity status,expression of uPA/MMPs . 2. Determine the relationship between PSAP and PCa growth and invasion in vivo. By using PCa cells expressing increased or decreased amounts of PSAP, we will examine the effect of PSAP on PCa cells growth, migratory, and invasive ability and in relation with expression level of B1-integrin, FAK activity, and uPA/MMPs in established primary or metastatic tumors.
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