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

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.

• Authors: Emelyn H Shroff, Livia S Eberlin, Vanessa M Dang, Arvin M Gouw, Meital Gabay, Stacey J Adam, David I Bellovin, Phuoc T Tran, William M Philbrick, Adolfo Garcia-Ocana, Stephanie C Casey, Yulin Li, Chi V Dang, Richard N Zare, Dean W Felsher
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 21 Pg. 6539-44 (May 26 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 25964345 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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