This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Chronic prostatitis, triggered by an infectious process, has been suggested as a promoter of prostate carcinogenesis and prostate cancer (PCa) progression;however, the mechanisms are poorly understood. We previously described the overexpression in PCa cells of a novel protein, prosaposin (PSAP). Serum PSAP levels increase with disease progression and were highest in metastatic PCa. Preliminary data show that down modulation of PSAP in PCa cell lines inhibits migration and invasion by decreasing beta-1A-integrin and Cathepsin D expression and activity. Our data also show that pro-inflammatory molecules such as lipopolysaccharide (LPS) and TNF-alpha greatly increase PSAP expression in PCa cells, which in turn increases their migration and invasion capabilities. These data provide a possible molecular mechanism linking chronic inflammation and the promotion of PCa. It also supports the hypothesis that PSAP production is stimulated in PCa cells by chronic inflammatory signals resulting in an increased invasion and metastasis. Inhibiting the PSAP pathway may inhibit the invasive and metastatic spread of PCa.
Our Aims are: 1. Determine the mechanisms by which PSAP regulates PCa cell migration and invasion. PSAP regulates ceramide (Cer) metabolism which in turn modulates ?1A integrin and cathepsin-D. Using stable PSAP-knock down cells, we will determine the molecular mechanisms involved in this regulation and its effects on PCa adhesion, migration, and invasion. 2. Determine the role of TLR-signaling on PSAP induction and stimulation of invasive phenotype in prostate cancer cells in vitro. Our data show that LPS increases PSAP protein expression through TLR4 signaling. We will determine the role of this and other TLR's in the induction and regulation of PSAP expression and invasion in PCa cells. 3. Determine the significance of TLR regulation of PSAP in invasive and metastatic behaviors during PCa progression in vivo. The results of this proposal will provide a mechanistic link between chronic inflammation and PCa, opening the possibility to develop novel forms of prevention and treatment.
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