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Title: Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis [Combined Proteomics and Metabolomics Analysis Reveals Grade-Dependent Metabolism Pathways in Kidney Cancer]

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. Altogether, our results offer a rationale to evaluate novel antimetabolic treatment strategies being developed in other disease settings as therapeutic strategiesmore » in RCC« less
Authors:
 [1] ;  [2] ;  [1] ;  [3] ;  [4] ;  [4] ;  [1] ;  [1] ;  [5] ;  [5] ;  [5] ;  [6] ;  [3] ;  [2] ;  [7]
  1. Univ. of California, Davis, CA (United States)
  2. Memorial Sloan Kettering Cancer Center, New York, NY (United States)
  3. Univ. of Milano-Bicocca, Monza (Italy)
  4. Univ. of Tennessee, Knoxville, TN (United States)
  5. Metabolon, Durham, NC (United States)
  6. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  7. Univ. of California, Davis, CA (United States); Sacramento VA Medical Center, Sacramento, CA (United States)
Publication Date:
Report Number(s):
LLNL-JRNL-654344
Journal ID: ISSN 0008-5472
Grant/Contract Number:
AC52-07NA27344
Type:
Accepted Manuscript
Journal Name:
Cancer Research
Additional Journal Information:
Journal Volume: 75; Journal Issue: 12; Journal ID: ISSN 0008-5472
Publisher:
American Association for Cancer Research
Research Org:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1408989

Wettersten, Hiromi I., Hakimi, A. Ari, Morin, Dexter, Bianchi, Cristina, Johnstone, Megan E., Donohoe, Dallas R., Trott, Josephine F., Aboud, Omran Abu, Stirdivant, Steven, Neri, Bruce, Wolfert, Robert, Stewart, Benjamin, Perego, Roberto, Hsieh, James J., and Weiss, Robert H.. Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis [Combined Proteomics and Metabolomics Analysis Reveals Grade-Dependent Metabolism Pathways in Kidney Cancer]. United States: N. p., Web. doi:10.1158/0008-5472.CAN-14-1703.
Wettersten, Hiromi I., Hakimi, A. Ari, Morin, Dexter, Bianchi, Cristina, Johnstone, Megan E., Donohoe, Dallas R., Trott, Josephine F., Aboud, Omran Abu, Stirdivant, Steven, Neri, Bruce, Wolfert, Robert, Stewart, Benjamin, Perego, Roberto, Hsieh, James J., & Weiss, Robert H.. Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis [Combined Proteomics and Metabolomics Analysis Reveals Grade-Dependent Metabolism Pathways in Kidney Cancer]. United States. doi:10.1158/0008-5472.CAN-14-1703.
Wettersten, Hiromi I., Hakimi, A. Ari, Morin, Dexter, Bianchi, Cristina, Johnstone, Megan E., Donohoe, Dallas R., Trott, Josephine F., Aboud, Omran Abu, Stirdivant, Steven, Neri, Bruce, Wolfert, Robert, Stewart, Benjamin, Perego, Roberto, Hsieh, James J., and Weiss, Robert H.. 2015. "Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis [Combined Proteomics and Metabolomics Analysis Reveals Grade-Dependent Metabolism Pathways in Kidney Cancer]". United States. doi:10.1158/0008-5472.CAN-14-1703. https://www.osti.gov/servlets/purl/1408989.
@article{osti_1408989,
title = {Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis [Combined Proteomics and Metabolomics Analysis Reveals Grade-Dependent Metabolism Pathways in Kidney Cancer]},
author = {Wettersten, Hiromi I. and Hakimi, A. Ari and Morin, Dexter and Bianchi, Cristina and Johnstone, Megan E. and Donohoe, Dallas R. and Trott, Josephine F. and Aboud, Omran Abu and Stirdivant, Steven and Neri, Bruce and Wolfert, Robert and Stewart, Benjamin and Perego, Roberto and Hsieh, James J. and Weiss, Robert H.},
abstractNote = {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. Altogether, our results offer a rationale to evaluate novel antimetabolic treatment strategies being developed in other disease settings as therapeutic strategies in RCC},
doi = {10.1158/0008-5472.CAN-14-1703},
journal = {Cancer Research},
number = 12,
volume = 75,
place = {United States},
year = {2015},
month = {5}
}