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Targeting myristoylation of Src family kinases for inhibition of prostate tumorig

靶向 Src 家族激酶的肉豆蔻酰化抑制前列腺肿瘤

基本信息

批准号：
8675209
负责人：
Houjian Cai
金额：
$ 29.99万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8675209
关键词：
Adenocarcinoma Affect Androgen Receptor Attenuated Binding Sites Biological Assay Cancer Patient Catalytic Domain Cell membrane Cells Complement Data Disease Disseminated Malignant Neoplasm Drug Targeting Epithelial Exhibits FGF10 gene Fibroblast Growth Factor Fibroblast Growth Factor Receptors Gene Mutation Goals Growth Factor Human Libraries Malignant Neoplasms Malignant neoplasm of prostate Mediating Medical Metastatic Neoplasm to the Bone Modification Myristic Acylation Site N-myristoyltransferase Natural regeneration Neoplasm Metastasis Paracrine Communication Phenotype Phosphotransferases Prostate Protein Tyrosine Kinase Proteins Research Personnel Role Signal Transduction Signal Transduction Pathway South Carolina Stream Tertiary Protein Structure Universities cancer cell castration resistant prostate cancer in vivo inhibitor/antagonist member mutant myristoylation neoplastic novel palmitoylation paracrine prevent prostate carcinogenesis public health relevance screening small molecule src-Family Kinases trafficking tumor tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The expression and activity of Src family kinases (SFKs) are highly elevated in numerous human cancers, including prostate cancer. SFKs are pleiotrophic activators in several signal transduction pathways. Targeting SFKs has a favorable inhibitory effect on proliferation of tumorigenic cells and bone metastasis in advanced castration-resistant prostate cancer patients. The SH4 domain of SFKs contains conserved sites for myristoylation, and palmitoylation modification depending on SFK members, which regulate SFKs trafficking intracellularly. The localization of SFKs at the cytoplasmic microdomain is critical to mediating cell signaling, exhibiting their activity, and illuminating their tumorigenic potential in cancer cells. Preliminary data suggest that myristoylated, but not palmitoylated, SFKs facilitate prostate tumorigenesis. In this proposal, investigators at the Medical University of South Carolina hypothesize that targeting myristoylation of SFKs inhibits their tumorigenic potential in prostate cancer. They will investigate if loss of myristoylation will attenuate SFK-induced tumorigenesis, inhibit Src kinase to interact with down- stream substrates such as androgen receptor, and suppress SFK-mediated paracrine signaling and over- expression of FGF10-induced tumorigenesis. The investigators will utilize myristoylation-defective SFK mutants and in complement a small molecule N-myristoyltransferase inhibitor, COPP-24, in a prostate regeneration assay to define the role of myristoylation in prostate tumorigenesis in vivo. This study will demonstrate that myristoylation of SFKs is a target for inhibiting prostate tumorigenesis and will evaluate the efficacy of a novel anti-neoplastic agent that blocks myristoylation of SFKs in treating prostate cancer.

描述（由申请人提供）：Src家族激酶（sfk）的表达和活性在包括前列腺癌在内的许多人类癌症中高度升高。sfk是多种信号转导通路中的多营养激活因子。靶向SFKs对晚期去势抵抗性前列腺癌患者的致瘤细胞增殖和骨转移具有良好的抑制作用。SFK的SH4结构域包含肉豆蔻酰化的保守位点，以及依赖于SFK成员的棕榈酰化修饰，这些修饰调节SFK在细胞内的运输。SFKs在细胞质微域的定位对于介导细胞信号传导、展示其活性和阐明其致瘤性至关重要