targeting myristoylation of Src family kinases for inhibition of prostate tumorig

靶向 Src 家族激酶的肉豆蔻酰化以抑制前列腺肿瘤

基本信息

批准号：
8976526
负责人：
Houjian Cai
金额：
$ 4.85万
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 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8976526
关键词：
Adenocarcinoma Affect Androgen Receptor Attenuated Binding Sites Biological Assay Cancer Patient Catalytic Domain Cell membrane Cells Complement DNA Sequence Alteration Data Disease Disseminated Malignant Neoplasm Drug Targeting Epithelial Exhibits FGF10 gene Fibroblast Growth Factor Fibroblast Growth Factor Receptors Goals Growth Factor Health 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 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）：在包括前列腺癌在内的许多人类癌症中，SRC家族激酶（SFK）的表达和活性高度升高。 SFK是多种信号转导途径中的多局营养活化剂。靶向SFK对晚期耐cast割前列腺癌患者的肿瘤细胞和骨转移的增殖具有良好的抑制作用。 SFK的SH4域包含保守的地点用于肉豆蔻酰化，并根据SFK成员的棕榈酰化修饰，这些成员会在细胞内调节SFKS贩运。 SFK在细胞质微域中的定位对于介导细胞信号，表现出活性并照亮其肿瘤症至关重要癌细胞的潜力。初步数据表明，肉豆蔻酰胺的，但没有棕榈酰化，SFK促进了前列腺肿瘤的发生。在这项提案中，南卡罗来纳州医科大学的研究人员假设，针对SFK的肉豆蔻酰化会抑制其在前列腺癌中的致癌潜力。他们将研究肉豆蔻酰化的丧失是否会衰减SFK诱导的肿瘤发生，抑制SRC激酶与诸如雄激素受体等沿流底物相互作用，并抑制SFK介导的旁氨基信号传导和FGF10诱导的肿瘤发生的过度表达。研究人员将利用肉豆蔻酰化缺陷的SFK突变体，并补充一个小分子N-米尔斯酯转移酶抑制剂COPP-24，在前列腺再生测定法中定义了肉豆蔻酰化在体内前列腺肿瘤中的作用。这项研究将表明，SFK的肉豆蔻酰化是抑制前列腺肿瘤发生的靶标，并将评估一种新型抗肿瘤剂的疗效，该抗肿瘤剂阻断了SFK在治疗前列腺癌中的肉豆蔻酰化。