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Cancer Res. 2015 Jun 15;75(12):2541-52. doi: 10.1158/0008-5472.CAN-14-1703. Epub 2015 May 7.

Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis.

Author information

1
Division of Nephrology, Department of Internal Medicine, School of Medicine, University of California, Davis, California.
2
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
3
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California.
4
Department of Health Sciences, School of Medicine, University of Milano-Bicocca, Monza, Italy.
5
Department of Nutrition, University of Tennessee, Knoxville, Tennessee.
6
Metabolon, Durham, North Carolina.
7
Lawrence Livermore National Laboratory, Livermore, California.
8
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
9
Division of Nephrology, Department of Internal Medicine, School of Medicine, University of California, Davis, California. Cancer Center, University of California, Davis, California. Medical Service, Sacramento VA Medical Center, Sacramento, California. rhweiss@ucdavis.edu.

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.

PMID:
25952651
PMCID:
PMC4470795
DOI:
10.1158/0008-5472.CAN-14-1703
[Indexed for MEDLINE]
Free PMC Article

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