PROSAPOSIN, A NOVEL INFLAMMATORY RESPONSE FACTOR FOR PROSTATE CANCER PROGRESSION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 由感染过程引发的慢性前列腺炎被认为是前列腺癌发生和前列腺癌(PCa)进展的促进剂；然而，其机制尚不清楚。我们先前描述了一种新的蛋白质--丙皂苷(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升高，在转移性前列腺癌中最高。初步数据显示，PSAP在PCa细胞系中的下调通过降低β-1A-整合素和组织蛋白酶D的表达和活性来抑制迁移和侵袭。我们的数据还显示，促炎分子，如脂多糖和肿瘤坏死因子-α，大大增加了PSAP在前列腺癌细胞中的表达，这反过来又增加了他们的迁移和侵袭能力。这些数据提供了一个可能的分子机制，将慢性炎症与前列腺癌的促进联系起来。它还支持PSAP的产生是由慢性炎症信号刺激Pca细胞产生的假说，从而导致侵袭和转移增加。抑制PSAP通路可能抑制PCa的侵袭和转移。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，神经酰胺代谢进而调节整合素和组织蛋白酶-D。利用稳定的PSAP敲除细胞，我们将确定参与这一调控的分子机制及其对PCa黏附、迁移和侵袭的影响。 2.确定TLR信号在前列腺癌PSAP诱导和体外侵袭表型刺激中的作用。我们的数据表明，内毒素通过TLR4信号通路增加PSAP蛋白的表达。我们将确定这个和其他TLR在诱导和调节PSAP表达和侵袭前列腺癌细胞中的作用。 3.确定PSAP的TLR调控在体内PCa侵袭和转移行为中的意义。这项建议的结果将提供慢性炎症和前列腺癌之间的机制联系，为开发新的预防和治疗形式打开了可能性。

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.