Kim Sungjin, Yang Xiangkun, Li Qianjin, Wu Meng, Costyn Leah, Beharry Zanna, Bartlett Michael G, Cai Houjian
From the Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602 and.
the Department of Chemistry and Physics, Florida Gulf Coast University, Fort Myers, Florida 33965.
J Biol Chem. 2017 Nov 10;292(45):18422-18433. doi: 10.1074/jbc.M117.798827. Epub 2017 Sep 22.
Exogenous fatty acids provide substrates for energy production and biogenesis of the cytoplasmic membrane, but they also enhance cellular signaling during cancer cell proliferation. However, it remains controversial whether dietary fatty acids are correlated with tumor progression. In this study, we demonstrate that increased Src kinase activity is associated with high-fat diet-accelerated progression of prostate tumors and that Src kinases mediate this pathological process. Moreover, in the prostate regeneration assay, host SCID mice carrying Src(Y529F)-transduced regeneration tissues were fed a low-fat diet or a high-fat diet and treated with vehicle or dasatinib. The high-fat diet not only accelerated Src-induced prostate tumorigenesis in mice but also compromised the inhibitory effect of the anticancer drug dasatinib on Src kinase oncogenic potential We further show that myristoylation of Src kinase is essential to facilitate Src-induced and high-fat diet-accelerated tumor progression. Mechanistically, metabolism of exogenous myristic acid increased the biosynthesis of myristoyl CoA and myristoylated Src and promoted Src kinase-mediated oncogenic signaling in human cells. Of the fatty acids tested, only exogenous myristic acid contributed to increased intracellular myristoyl CoA levels. Our results suggest that targeting Src kinase myristoylation, which is required for Src kinase association at the cellular membrane, blocks dietary fat-accelerated tumorigenesis Our findings uncover the molecular basis of how the metabolism of myristic acid stimulates high-fat diet-mediated prostate tumor progression.
外源性脂肪酸为能量产生和细胞质膜的生物合成提供底物，但它们也在癌细胞增殖过程中增强细胞信号传导。然而，膳食脂肪酸是否与肿瘤进展相关仍存在争议。在本研究中，我们证明Src激酶活性增加与高脂饮食加速前列腺肿瘤进展相关，且Src激酶介导这一病理过程。此外，在前列腺再生试验中，将携带经Src(Y529F)转导的再生组织的宿主SCID小鼠喂食低脂饮食或高脂饮食，并给予溶剂或达沙替尼治疗。高脂饮食不仅加速了小鼠中Src诱导的前列腺肿瘤发生，还削弱了抗癌药物达沙替尼对Src激酶致癌潜力的抑制作用。我们进一步表明，Src激酶的肉豆蔻酰化对于促进Src诱导的和高脂饮食加速的肿瘤进展至关重要。从机制上讲，外源性肉豆蔻酸的代谢增加了肉豆蔻酰辅酶A和肉豆蔻酰化Src的生物合成，并促进了人细胞中Src激酶介导的致癌信号传导。在所测试的脂肪酸中，只有外源性肉豆蔻酸导致细胞内肉豆蔻酰辅酶A水平升高。我们的结果表明，靶向Src激酶肉豆蔻酰化（这是Src激酶在细胞膜上结合所必需的）可阻断膳食脂肪加速的肿瘤发生。我们的发现揭示了肉豆蔻酸代谢如何刺激高脂饮食介导的前列腺肿瘤进展的分子基础。
