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Protein myristoylation links a high fat diet with prostate tumor progression in mice
Author(s) -
Cai Houjian,
Kim Sunjin
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.791.1
Subject(s) - proto oncogene tyrosine protein kinase src , prostate cancer , dasatinib , myristoylation , prostate , biology , cancer research , carcinogenesis , tumor progression , kinase , cancer , endocrinology , medicine , chemistry , microbiology and biotechnology , signal transduction , phosphorylation , tyrosine kinase
Objective of the study Exogenous fatty acids provide substrates for energy production and the 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. Additionally, the molecular mechanisms explaining the effect of dietary fatty acids in promoting prostate cancer progression remains unknown. Statement of Methods In this study, prostate regeneration assay and prostate cancer cell xenografts were applied to study if and how a high fat diet promotes tumor progression in vivo. The amount of Acyl‐CoAs were analyzed by LC–MS/MS analysis. Myristoylation of Src kinase was detected by Click chemistry. Additionally, to examine the molecular mechanisms, proteins were fractionated into cytosol and membrane fraction. Expression levels of Src kinase were detected by immunoblotting. Summary of the results 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 in vivo prostate regeneration assay, host SCID mice carrying Src(Y529F) transduced regeneration tissues were fed with 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 in vivo . 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. Conclusion Our results indicate that targeting Src kinase myristoylation, which is required for Src kinase association at the cellular membrane, blocks dietary fat accelerated tumorigenesis in vivo . Our findings uncover a molecular basis, which the biosynthesis of myristoyl‐CoA elevates the expression of myristoyl‐Src, and accelerates Src mediated prostate tumor progression in a high fat diet. Support or Funding Information NIH (R01CA172495) and DOD (W81XWH‐15‐1‐0507)