Role of Raf Kinase Inhibitory Protein in Prostate Cancer

Raf 激酶抑制蛋白在前列腺癌中的作用

• 批准号: 7322528
• 负责人: MARSHA R ROSNER
• 金额: $ 29.71万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-08 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7322528
• 关键词: Androgens; Behavior; Binding; Biological Assay; Cell model; Cells; Chemicals; Clinical; Differentiation and Growth; Drug Delivery Systems; Ectopic Expression; Family; Gene Proteins; Genetic Transcription; Goals; Growth; In Vitro; Invasive; LNCaP; Laboratories; MAPK1 gene; MAPK3 gene; Malignant - descriptor; Malignant neoplasm of prostate; Mediator of activation protein; Membrane; Metastasis Suppressor Proteins; Metastatic Lesion; Methods; Mitogen-Activated Protein Kinases; Mitotic; Molecular; Molecular Profiling; Neoplasm Metastasis; Neoplastic Processes; Nonmetastatic; Normal Cell; Numbers; Penetration; Peptide Library; Peptides; Phenotype; Phosphorylation; Phosphorylation Site; Proline; Prostate; Prostatic Neoplasms; Protein Binding Domain; Protein Kinase C; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins c-raf; Ras/Raf; Reagent; Regulation; Reporting; Role; Signal Transduction; Signaling Protein; Testing; Therapeutic; Tissue Sample; cancer cell; cell growth; cell type; in vivo; inhibitor/antagonist; member; mutant; neoplastic cell; novel; preclinical study; protein expression; protein function; protein structure; raf Kinases; raf-1 Protein; small hairpin RNA; therapeutic target; tumor; tumor progression

DESCRIPTION (provided by applicant): Dysregulation of growth signaling cascades is a key step in the initiation and malignant progression of prostate cancers. Among the main mediators of signals in proliferative cells are the mitogen-activated protein kinases (MAPKs), a super-family of highly homologous proline-directed serine/threonine kinases that participate in the transduction of growth and differentiation-promoting signals. The Ras/Raf kinase cascade that leads to activation of ERK1 and ERK2, two members of the ERK subfamily of MAPKs, is required for normal cell growth as well as neoplastic processes. Activation of this signaling cascade is correlated with prostate cancer progression and androgen-independence and thus is an important therapeutic target. One of the modulators of Raf kinase is Raf Kinase Inhibitory Protein (RKIP). Recent studies from our laboratory have shown that RKIP regulates Raf activation via interaction at S153; phosphorylation of S153 by activators of protein kinase C release RKIP, enabling subsequent activation of Raf. We have also shown that RKIP regulates mitotic progression in a number of cell types. An exciting new biologic function for RKIP in the suppression of prostate cancer metastasis has recently been reported. Specifically, immunohistochemical analysis of clinical tissue samples revealed expression of RKIP in primary prostate cancer but not in metastatic lesions. Functional in vivo studies showed that ectopic expression of RKIP suppressed invasion in vitro and metastasis in vivo in the well-characterized metastatic C42 human prostate cancer cell model. Conversely, decreasing the level of RKIP in nonmetastatic LNCaP cells promoted their invasive ability in vitro. Taken together, these studies implicate RKIP as a metastasis suppressor protein. We anticipate that identification of the mechanism by which RKIP signals to suppress metastasis will provide information necessary to understanding the molecular underpinnings of prostate cancer metastasis. The goal of this proposal is to relate RKIP structure to its function as a metastasis suppressor and then use this information to develop therapeutic reagents that modulate or mimic RKIP biologic function. Specifically, we plan to: 1) Identify the targets of RKIP action in prostate tumor cells; and 2) Generate inhibitors or potentiators of Raf-1 or RKIP. The reagents developed in these studies could be used in combination with other tumor therapies to suppress specific steps in the metastatic cascade.

描述（由申请人提供）：生长信号级联的失调是前列腺癌发生和恶性进展的关键步骤。增殖细胞中的主要信号介质是丝裂原活化蛋白激酶（MAPKs），这是一个高度同源的脯氨酸定向丝氨酸/苏氨酸激酶超家族，参与生长和分化促进信号的转导。Ras/Raf激酶级联导致ERK1和ERK2 （MAPKs的ERK亚家族的两个成员）的激活，是正常细胞生长和肿瘤过程所必需的。该信号级联的激活与前列腺癌的进展和雄激素不依赖性相关，因此是一个重要的治疗靶点。Raf激酶的调节剂之一是Raf激酶抑制蛋白（RKIP）。我们实验室最近的研究表明，RKIP通过S153的相互作用调节Raf的激活；蛋白激酶C的激活剂使S153磷酸化，释放RKIP，使Raf随后激活。我们还表明，RKIP调节许多细胞类型的有丝分裂进程。最近报道了RKIP抑制前列腺癌转移的一个令人兴奋的新生物学功能。具体来说，临床组织样本的免疫组织化学分析显示，RKIP在原发性前列腺癌中表达，而在转移性病变中没有表达。体内功能研究表明，在具有良好特征的转移性C42人前列腺癌细胞模型中，RKIP的异位表达抑制了体外侵袭和体内转移。相反，降低非转移性LNCaP细胞的RKIP水平可提高其体外侵袭能力。综上所述，这些研究提示RKIP是一种转移抑制蛋白。我们期望通过RKIP信号抑制转移的机制的鉴定将为理解前列腺癌转移的分子基础提供必要的信息。本研究的目标是将RKIP结构与其作为转移抑制因子的功能联系起来，然后利用这些信息开发调节或模拟RKIP生物功能的治疗试剂。具体而言，我们计划：1)确定RKIP在前列腺肿瘤细胞中的作用靶点；2)生成Raf-1或RKIP的抑制剂或增强剂。在这些研究中开发的试剂可以与其他肿瘤疗法联合使用，以抑制转移级联中的特定步骤。