MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism

Proc Natl Acad Sci U S A. 2015 May 26;112(21):6539-44. doi: 10.1073/pnas.1507228112. Epub 2015 May 11.

Abstract

The MYC oncogene is frequently mutated and overexpressed in human renal cell carcinoma (RCC). However, there have been no studies on the causative role of MYC or any other oncogene in the initiation or maintenance of kidney tumorigenesis. Here, we show through a conditional transgenic mouse model that the MYC oncogene, but not the RAS oncogene, initiates and maintains RCC. Desorption electrospray ionization-mass-spectrometric imaging was used to obtain chemical maps of metabolites and lipids in the mouse RCC samples. Gene expression analysis revealed that the mouse tumors mimicked human RCC. The data suggested that MYC-induced RCC up-regulated the glutaminolytic pathway instead of the glycolytic pathway. The pharmacologic inhibition of glutamine metabolism with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide impeded MYC-mediated RCC tumor progression. Our studies demonstrate that MYC overexpression causes RCC and points to the inhibition of glutamine metabolism as a potential therapeutic approach for the treatment of this disease.

Keywords: MYC oncogene; desorption electrospray ionization mass spectrometry imaging; glutamine metabolism; renal cell carcinoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Disease Progression
  • Enzyme Inhibitors / pharmacology
  • Genes, myc*
  • Genes, ras
  • Glutaminase / antagonists & inhibitors
  • Glutaminase / metabolism
  • Glutamine / metabolism*
  • Humans
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Lipid Metabolism
  • Mice
  • Mice, SCID
  • Mice, Transgenic
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Spectrometry, Mass, Electrospray Ionization
  • Sulfides / pharmacology
  • Thiadiazoles / pharmacology
  • Up-Regulation

Substances

  • Enzyme Inhibitors
  • RNA, Messenger
  • RNA, Neoplasm
  • Sulfides
  • Thiadiazoles
  • bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide
  • Glutamine
  • Glutaminase