Targeting myristoylation of Src family kinases for inhibition of prostate tumorig

描述(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)的表达和活性都高度升高。SFK是多种信号转导途径中的多营养激活剂。靶向SFK对晚期去势抵抗前列腺癌患者的成瘤细胞增殖和骨转移有良好的抑制作用。SFK的SH4结构域包含依赖于SFK成员的肉豆蔻酰化和棕榈酰化修饰的保守部位，调节SFK在细胞内的转运。SFKs在细胞质微区的定位对于介导细胞信号、显示其活性和阐明其致癌作用至关重要。 癌细胞中的潜在性。初步数据表明，肉豆蔻酰化而不是棕榈酰化的SFK促进了前列腺癌的发生。在这项提案中，南卡罗来纳医科大学的研究人员假设，靶向SFK的肉豆蔻酰化可以抑制它们在前列腺癌中的致瘤潜力。他们将研究肉豆蔻化缺失是否会减弱SFK诱导的肿瘤形成，抑制Src激酶与雄激素受体等下游底物的相互作用，并抑制SFK介导的旁分泌信号和FGF10诱导的肿瘤形成的过度表达。研究人员将利用肉豆蔻酰化缺陷的SFK突变体，并在前列腺再生试验中补充小分子N-肉豆蔻酰基转移酶抑制剂CoPP-24，以确定肉豆蔻酰化在体内前列腺癌发生中的作用。 本研究将证明SFKs的肉豆蔻酰化是抑制前列腺癌发生的一个靶点，并将评估一种新型的抗肿瘤药物在治疗前列腺癌中的疗效。

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.