title: Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis.
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.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, School of Medicine, University of California, Davis, California.
authors.forename: Hiromi I
authors.initials: HI
authors.lastname: Wettersten
authors.affiliation: Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: A Ari
authors.initials: AA
authors.lastname: Hakimi
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California.
authors.forename: Dexter
authors.initials: D
authors.lastname: Morin
authors.affiliation: Department of Health Sciences, School of Medicine, University of Milano-Bicocca, Monza, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bianchi
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Johnstone
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee.
authors.forename: Dallas R
authors.initials: DR
authors.lastname: Donohoe
authors.affiliation: Division of Nephrology, Department of Internal Medicine, School of Medicine, University of California, Davis, California.
authors.forename: Josephine F
authors.initials: JF
authors.lastname: Trott
authors.affiliation: Division of Nephrology, Department of Internal Medicine, School of Medicine, University of California, Davis, California.
authors.forename: Omran Abu
authors.initials: OA
authors.lastname: Aboud
authors.affiliation: Metabolon, Durham, North Carolina.
authors.forename: Steven
authors.initials: S
authors.lastname: Stirdivant
authors.affiliation: Metabolon, Durham, North Carolina.
authors.forename: Bruce
authors.initials: B
authors.lastname: Neri
authors.affiliation: Metabolon, Durham, North Carolina.
authors.forename: Robert
authors.initials: R
authors.lastname: Wolfert
authors.affiliation: Lawrence Livermore National Laboratory, Livermore, California.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Stewart
authors.affiliation: Department of Health Sciences, School of Medicine, University of Milano-Bicocca, Monza, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Perego
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: James J
authors.initials: JJ
authors.lastname: Hsieh
authors.affiliation: 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.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Weiss
mesh_terms: D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology*; D055432:Metabolomics / Q000379:methods; D060787:Neoplasm Grading; D040901:Proteomics / Q000379:methods; D014162:Transfection