Myristoylation of Src kinase mediates Src-induced and high-fat diet-accelerated prostate tumor progression in mice

J Biol Chem. 2017 Nov 10;292(45):18422-18433. doi: 10.1074/jbc.M117.798827. Epub 2017 Sep 22.

Abstract

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 in vivo 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 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. Our results suggest 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 the molecular basis of how the metabolism of myristic acid stimulates high-fat diet-mediated prostate tumor progression.

Keywords: Src; diet; fatty acid; prostate cancer; protein myristoylation.

MeSH terms

  • Acylation / drug effects
  • Amino Acid Substitution
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • CSK Tyrosine-Protein Kinase
  • Cell Line, Tumor
  • Diet, High-Fat / adverse effects*
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, SCID
  • Mutation
  • Myristic Acid / metabolism
  • Neoplasm Proteins / agonists
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Prostate / drug effects*
  • Prostate / metabolism
  • Prostate / pathology
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / etiology
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Processing, Post-Translational / drug effects*
  • Proto-Oncogene Proteins pp60(c-src) / chemistry
  • Proto-Oncogene Proteins pp60(c-src) / genetics
  • Proto-Oncogene Proteins pp60(c-src) / metabolism*
  • RNA Interference
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays
  • src-Family Kinases / antagonists & inhibitors*
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Myristic Acid
  • CSK Tyrosine-Protein Kinase
  • Proto-Oncogene Proteins pp60(c-src)
  • src-Family Kinases
  • CSK protein, human