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Tracking Metabolic Rewiring of Cancer Metabolism in Humans Using Isotope-Resolved NMR

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NMR-Based Metabolomics

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2037))

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Abstract

Altered metabolism is considered one of the hallmarks of cancer. The findings that malignant brain tumors and brain metastases utilize acetate as an alternative nutrient are relatively recent and offer new avenues for investigation of altered metabolism in human cancers. Here, we describe comprehensively the details of the 13C NMR-based isotopomer methodology to measure in vivo acetate utilization in brain tumor patients, including the contribution from acetate metabolism of peripheral tissues. Methods described in this chapter can be readily extended to other cancer types.

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References

  1. Strisower EH, Kohler GD, Chaikoff IL (1952) Incorporation of acetate carbon into glucose by liver slices from normal and alloxan-diabetic rats. J Biol Chem 198:115–126

    CAS  PubMed  Google Scholar 

  2. Weinman EO, Strisower EH, Chaikoff IL (1957) Conversion of fatty acids to carbohydrate: applications of isotopes to this problem and the role of Krebs cycle as a synthetic pathway. Physiol Rev 37:252–272

    Article  CAS  Google Scholar 

  3. Coxon RV, Robinson RJ (1959) Movements of radioactive carbon dioxide within the animal body during oxidation of 14C-labeled substances. J Physiol 147:487–570

    Article  CAS  Google Scholar 

  4. Coxon RV, Robinson RJ (1959) The transport of radioactive carbon dioxide in the blood stream of the dog after administration of radioactive biocarbonate. J Physiol 147:469–486

    Article  CAS  Google Scholar 

  5. Ramanathan A, Wang C, Schreiber SL (2005) Peturbational profiling of a cell-line model of tumorigenesis by using metabolic maesurements. Proc Natl Acad Sci U S A 102:5992–5997

    Article  CAS  Google Scholar 

  6. Forbes NS, Meadows AL, Clark DS et al (2006) Estradiol stimulates the biosynthetic pathways of breast cancer cells: detection by metabolic flux analysis. Metab Eng 8:639–652

    Article  CAS  Google Scholar 

  7. Lee J, Kotliarova S, Kotliarov Y et al (2006) Tumor stem cells derived from glioblastoma cultured in bFGF and EGF more closely mirror the phenotyope and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9:391–403

    Article  CAS  Google Scholar 

  8. Marian CO, Cho SK, McEllin BM et al (2010) The telomerase antagonist, imetelstat, effectively targets glioblastoma tumor-initiating cells leading to decreased proliferation and tumor growth. Clin Cancer Res 16:154–163

    Article  CAS  Google Scholar 

  9. Chance EM, Seeholzer SH, Kobayashi K et al (1983) Mathematical analysis of isotope labeling in the citric acid cycle with applications to 13C NMR studies in perfused rat hearts. J Biol Chem 258:13785–13794

    CAS  PubMed  Google Scholar 

  10. London RE (1987) 13C labeling in studies of metabolic regulation. Prog NMR Spectrosc 20:337–383

    Article  Google Scholar 

  11. Ward PS, Thompson CB (2012) Metabolic reprogramming: a cancer Hallmark even Warburg did not anticipate. Cancer Cell 21:297–308

    Article  CAS  Google Scholar 

  12. Maher EA, Marin-Valencia I, Bachoo RM et al (2012) Metabolism of [U-13C]glucose in human brain tumors in vivo. NMR Biomed 25:1234–1244

    Article  CAS  Google Scholar 

  13. Mashimo T, Pichumani K, Vemireddy V et al (2014) Acetate is a bioenergetics substrate for human glioblastoma and brain metastases. Cell 159:1603–1614

    Article  CAS  Google Scholar 

  14. Pichumani K, Mashimo T, Baek H-M et al (2015) Conditions for 13C NMR detection of 2-Hydroxyglutarate in tissue extracts from isocitrate dehydrogenase-mutated gliomas. Anal Biochem 481:4–6

    Article  CAS  Google Scholar 

  15. Pichumani K, Mashimo T, Vemireddy V et al (2016) Hepatic gluconeogenesis influences 13C enrichment in lactate in human brain tumors during metabolism of [1,2-13C]acetate. Neurochem Int 97:133–136

    Article  CAS  Google Scholar 

  16. Maher EA, Pichumani K, Sarode V et al (2016) Differential metabolism of glucose and acetate in mitochondria of early stage breast cancer in vivo. Proc Intl Soc Mag Reson Med 24:841

    Google Scholar 

  17. Pichumani K, Mashimo T, Vemireddy V et al (2017) Measurement of 13C turnover into glutamate and glutamine pools in brain tumor patients. FEBS Lett 591:3548–3554

    Article  CAS  Google Scholar 

  18. Courtney KD, Bezwada D, Mashimo T et al (2018) Isotopic tracing of human clear cell renal cell carcinomas demonstrates suppressed glucose oxidation In Vivo. Cell Metab 28:793–800

    Article  CAS  Google Scholar 

  19. Malloy CR, Thompson JR, Jeffrey FH et al (1990) Contributions of exogenous substrates to acetyl coenzyme a: measurement by 13C NMR under non-steady-state conditions. Biochemistry 29:6756–6761

    Article  CAS  Google Scholar 

  20. Cerdan S, Kunnecke B, Seelig J et al (1990) Cerebral metabolism of [1,2-13C2]acetate as detected by in Vivo and in Vitro 13C NMR. J Biol Chem 265:12916–12926

    CAS  PubMed  Google Scholar 

  21. DeBerardinis RJ, Mancuso A, Daikhin E et al (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A 104:345–350

    Article  Google Scholar 

  22. Tardito S, Oudin A, Ahmed SU et al (2015) Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Nat Chem Biol 17:1556–1568

    CAS  Google Scholar 

  23. Venneti S, Dunphy MP, Zhang H et al (2015) Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo. Sci Transl Med 7:274ra17

    Article  Google Scholar 

  24. Szczepaniak L, Babcock EE, Malloy CR et al (1996) Oxidation of acetate in rabbit skeletal muscle: detection by 13C NMR spectroscopy in vivo. Magn Reson Med 36:451–457

    Article  CAS  Google Scholar 

  25. Befroy DE, Perry RJ, Jain N et al (2014) Direct assessment of hepatic mitochondrial oxidative and anaplerotic fluxes in humans using dynamic 13C magnetic resonance spectroscopy. Nat Med 20:98–102

    Article  CAS  Google Scholar 

  26. Valencia IM, Cho SK, Rakjeja D et al (2012) Glucose metabolism via the pentose phosphate pathway, glycolysis and Krebs cycle in an Orthotopic mouse model of human brain tumors. NMR Biomed 25:1177–1186

    Article  Google Scholar 

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Acknowledgments

This work was supported by Donna and Kenneth Peak, The Kenneth R. Peak Foundation, The Kenneth R. Peak Brain and Pituitary Tumor Treatment Center at Houston Methodist Hospital, The Houston Methodist Foundation, The Taub Foundation, The Pauline Sterne Wolff Foundation, The Veralan Foundation, The Marilee A. and Gary M. Schwarz Foundation, The John S. Dunn Foundation and The McKone Family Foundation. We are grateful to the many patients and their families who have participated in our studies, and who are dedicated to join us in our fight against brain cancer.

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Authors and Affiliations

  1. Kenneth R. Peak Brain and Pituitary Tumor Treatment Center and the Department of Neurosurgery, Houston Methodist Hospital and Research Institute, Houston, TX, USA

    Kumar Pichumani

  2. Weill Cornell Medical College, New York, NY, USA

    Kumar Pichumani

Authors
  1. Kumar Pichumani
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Correspondence to Kumar Pichumani .

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Editors and Affiliations

  1. Northwest Metabolomics Research Center, Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA

    G. A. Nagana Gowda

  2. Northwest Metabolomics Research Center, Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Fred Hutch Cancer Research Center, Seattle, WA, USA

    Daniel Raftery

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Pichumani, K. (2019). Tracking Metabolic Rewiring of Cancer Metabolism in Humans Using Isotope-Resolved NMR. In: Gowda, G., Raftery, D. (eds) NMR-Based Metabolomics. Methods in Molecular Biology, vol 2037. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9690-2_10

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  • DOI: https://doi.org/10.1007/978-1-4939-9690-2_10

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-9689-6

  • Online ISBN: 978-1-4939-9690-2

  • eBook Packages: Springer Protocols

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