PROSAPOSIN, A NOVEL INFLAMMATORY RESPONSE FACTOR FOR PROSTATE CANCER PROGRESSION

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 表示子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 慢性前列腺炎，由感染过程引发，已被认为是前列腺癌发生和前列腺癌（PCa）进展的促进剂;然而，其机制知之甚少。 我们先前描述了一种新的蛋白质，鞘脂激活蛋白原（PSAP）在前列腺癌细胞中的过表达。血清PSAP水平随着疾病进展而增加，并且在转移性PCa中最高。初步数据显示，PCa细胞系中PSAP的下调通过降低β-1A-整联蛋白和组织蛋白酶D的表达和活性来抑制迁移和侵袭。我们的数据还表明，促炎分子如脂多糖（LPS）和TNF-α大大增加了PSAP在PCa细胞中的表达，这反过来又增加了它们的迁移和侵袭能力。这些数据提供了一种可能的分子机制，将慢性炎症和PCa的促进联系起来。它还支持了慢性炎症信号刺激PCa细胞中PSAP产生，导致侵袭和转移增加的假设。抑制PSAP通路可抑制PCa的侵袭性和转移性扩散。我们的目标是： 1.确定PSAP调节PCa细胞迁移和侵袭的机制。PSAP调节神经酰胺（Cer）代谢，进而调节1A整合素和组织蛋白酶D。 使用稳定的PSAP敲低细胞，我们将确定参与这种调节的分子机制及其对PCa粘附，迁移和侵袭的影响。 2.确定TLR信号传导对体外前列腺癌细胞中PSAP诱导和刺激侵袭表型的作用。我们的数据显示LPS通过TLR 4信号传导增加PSAP蛋白表达。我们将确定这种和其他TLR在诱导和调节PSAP表达和PCa细胞侵袭中的作用。 3.确定TLR调节PSAP在体内PCa进展过程中侵袭和转移行为的意义。该提案的结果将提供慢性炎症和PCa之间的机制联系，为开发新的预防和治疗形式提供可能性。

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.