Grade-dependent metabolic reprogramming in kidney cancer revealed by combined proteomics and metabolomics analysis

Hiromi I. Wettersten, A. Ari Hakimi, Dexter Morin, Cristina Bianchi, Megan E. Johnstone, Dallas R. Donohoe, Josephine F. Trott, Omran Abuaboud, Steven Stirdivant, Bruce Neri, Robert Wolfert, Benjamin Stewart, Roberto Perego, James J. Hsieh, Robert H Weiss

Research output: Contribution to journalArticle

96 Scopus citations

Abstract

Kidney cancer [or renal cell carcinoma (RCC)] is known as "the internist's tumor" because it has protean systemic manifestations, suggesting that it utilizes complex, nonphysiologic metabolic pathways. Given the increasing incidence of this cancer and its lack of effective therapeutic targets, we undertook an extensive analysis of human RCC tissue employing combined grade-dependent proteomics and metabolomics analysis to determine how metabolic reprogramming occurring in this disease allows it to escape available therapeutic approaches. After validation experiments in RCC cell lines that were wild-type or mutant for the Von Hippel-Lindau tumor suppressor, in characterizing higher-grade tumors, we found that the Warburg effect is relatively more prominent at the expense of the tricarboxylic acid cycle and oxidative metabolism in general. Further, we found that the glutamine metabolism pathway acts to inhibit reactive oxygen species, as evidenced by an upregulated glutathione pathway, whereas the β-oxidation pathway is inhibited, leading to increased fatty acylcarnitines. In support of findings from previous urine metabolomics analyses, we also documented tryptophan catabolism associated with immune suppression, which was highly represented in RCC compared with other metabolic pathways. Together, our results offer a rationale to evaluate novel antimetabolic treatment strategies being developed in other disease settings as therapeutic strategies in RCC.

Original languageEnglish (US)
Pages (from-to)2541-2552
Number of pages12
JournalCancer Research
Volume75
Issue number12
DOIs
StatePublished - Jun 15 2015

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Wettersten, H. I., Hakimi, A. A., Morin, D., Bianchi, C., Johnstone, M. E., Donohoe, D. R., Trott, J. F., Abuaboud, O., Stirdivant, S., Neri, B., Wolfert, R., Stewart, B., Perego, R., Hsieh, J. J., & Weiss, R. H. (2015). Grade-dependent metabolic reprogramming in kidney cancer revealed by combined proteomics and metabolomics analysis. Cancer Research, 75(12), 2541-2552. https://doi.org/10.1158/0008-5472.CAN-14-1703