PROSAPOSIN, A NOVEL INFLAMMATORY RESPONSE FACTOR FOR PROSTATE CANCER PROGRESSION

PROSAPOSIN，一种前列腺癌进展的新型炎症反应因子

• 批准号: 8360448
• 负责人: SHAHRIAR KOOCHEKPOUR
• 金额: $ 20.04万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360448
• 关键词: Adhesions; Behavior; Cathepsins; Cells; Ceramides; Chronic; Chronic Prostatitis; Data; Disease Progression; Funding; Grant; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Integrins; Link; Lipopolysaccharides; Louisiana; Malignant neoplasm of prostate; Mentors; Metabolism; Metastatic Prostate Cancer; Molecular; National Center for Research Resources; Neoplasm Metastasis; PC3 cell line; Pathway interactions; Phenotype; Prevention; Principal Investigator; Process; Production; Proteins; Regulation; Research; Research Infrastructure; Research Personnel; Resources; Role; Serum; Signal Transduction; Source; TLR4 gene; Tumor Necrosis Factor-alpha; United States National Institutes of Health; cancer cell; cell motility; cost; human TNF protein; in vivo; knock-down; migration; novel; overexpression; promoter; prostate carcinogenesis; protein expression; tumor progression

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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 由传染过程触发的慢性前列腺炎已被建议作为前列腺癌发生和前列腺癌（PCA）进展的启动子。但是，这些机制知之甚少。我们先前描述了新型蛋白质Prousaposin（PSAP）的PCA细胞中的过表达。血清PSAP水平随疾病进展而增加，在转移性PCA中最高。初步数据表明，PCA细胞系中PSAP的调节通过降低β-1A-凝集素和组织蛋白酶D的表达和活性来抑制迁移和侵袭。我们的数据还表明，促炎性分子（例如脂多糖（LPS）和TNF-Alpha）在PCA细胞中大大增加了PSAP的表达，进而增加了它们的迁移和侵袭能力。这些数据提供了连接慢性感染和PCA促进的可能分子机制。它还支持以下假设：PCA细胞中PSAP的产生通过慢性炎症信号刺激，从而导致侵袭和转移增加。抑制PSAP途径可能会抑制PCA的侵袭性和转移扩散。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，从而调节»整联蛋白和组织蛋白酶-D。我们将使用稳定的PSAP敲除细胞，确定该调节所涉及的分子机制及其对PCA粘合剂，迁移和侵袭的影响。 2。确定TLR信号在体外前列腺癌细胞中侵入性表型刺激的作用。我们的数据表明，LPS通过TLR4信号传导增加了PSAP蛋白表达。我们将确定该和其他TLR在PCA细胞中PSAP表达和侵袭的诱导和调节中的作用。 3。确定体内PCA进展过程中PSAP侵入性和转移行为的TLR调节的显着性。该提案的结果将提供慢性炎症和PCA之间的机械联系，从而开辟了开发新形式的预防和治疗形式的可能性。