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

Emelyn H. Shroff, Livia S. Eberlin, Vanessa M. Dang, Arvin M. Gouw, Meital Gabay, Stacey J. Adam, David I. Bellovin, Phuoc T. Trand, William M. Philbrick, Adolfo Garcia-Ocana, Stephanie C. Casey, Yulin Li, Chi V. Dang, Richard N. Zare, Dean W. Felsher

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)6539-6544
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number21
DOIs
StatePublished - May 26 2015
Externally publishedYes

Fingerprint

Glutamine
Oncogenes
Renal Cell Carcinoma
Transgenic Mice
Neoplasms
Carcinogenesis
Maintenance
Kidney
Lipids
Gene Expression

Keywords

  • Desorption electrospray ionization mass spectrometry imaging
  • Glutamine metabolism
  • MYC oncogene
  • Renal cell carcinoma

ASJC Scopus subject areas

  • General

Cite this

MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. / Shroff, Emelyn H.; Eberlin, Livia S.; Dang, Vanessa M.; Gouw, Arvin M.; Gabay, Meital; Adam, Stacey J.; Bellovin, David I.; Trand, Phuoc T.; Philbrick, William M.; Garcia-Ocana, Adolfo; Casey, Stephanie C.; Li, Yulin; Dang, Chi V.; Zare, Richard N.; Felsher, Dean W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 21, 26.05.2015, p. 6539-6544.

Research output: Contribution to journalArticle

Shroff, EH, Eberlin, LS, Dang, VM, Gouw, AM, Gabay, M, Adam, SJ, Bellovin, DI, Trand, PT, Philbrick, WM, Garcia-Ocana, A, Casey, SC, Li, Y, Dang, CV, Zare, RN & Felsher, DW 2015, 'MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 21, pp. 6539-6544. https://doi.org/10.1073/pnas.1507228112
Shroff, Emelyn H. ; Eberlin, Livia S. ; Dang, Vanessa M. ; Gouw, Arvin M. ; Gabay, Meital ; Adam, Stacey J. ; Bellovin, David I. ; Trand, Phuoc T. ; Philbrick, William M. ; Garcia-Ocana, Adolfo ; Casey, Stephanie C. ; Li, Yulin ; Dang, Chi V. ; Zare, Richard N. ; Felsher, Dean W. / MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 21. pp. 6539-6544.
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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.",
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AU - Gabay, Meital

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AU - Bellovin, David I.

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AU - Casey, Stephanie C.

AU - Li, Yulin

AU - Dang, Chi V.

AU - Zare, Richard N.

AU - Felsher, Dean W.

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AB - 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.

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