targeting myristoylation of Src family kinases for inhibition of prostate tumorig

描述（由申请人提供）：Src家族激酶（SFK）的表达和活性在许多人类癌症（包括前列腺癌）中高度升高。SFK是多种信号转导途径中的多效性激活剂。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。SFKs的SH 4结构域含有肉豆蔻酰化和棕榈酰化修饰的保守位点，这些位点依赖于SFK成员，调节SFKs在细胞内的运输。SFKs在细胞质微区的定位对于介导细胞信号传导、显示其活性和阐明其致瘤性至关重要。 在癌细胞中的潜力。初步数据表明，肉豆蔻酰化，而不是棕榈酰化，SFKs促进前列腺肿瘤的发生。在这项提议中，南卡罗来纳州医科大学的研究人员假设，靶向SFKs的豆蔻酰化抑制了它们在前列腺癌中的致瘤潜力。他们将研究肉豆蔻酰化的丧失是否会减弱SFK诱导的肿瘤发生，抑制Src激酶与下游底物如雄激素受体相互作用，并抑制SFK介导的旁分泌信号传导和FGF 10诱导的肿瘤发生的过表达。研究人员将利用豆蔻酰化缺陷的SFK突变体和补充小分子N-豆蔻酰转移酶抑制剂COPP-24，在前列腺再生试验中确定豆蔻酰化在体内前列腺肿瘤发生中的作用。 这项研究将证明，豆蔻酰化的SFKs是一个目标，抑制前列腺肿瘤的发生，并将评估一种新的抗肿瘤药物，阻断豆蔻酰化的SFKs治疗前列腺癌的疗效。

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.