Metabolism of [U-13C]glucose in human brain tumors in vivo

Elizabeth A. Maher, Isaac Marin-Valencia, Robert M. Bachoo, Tomoyuki Mashimo, Jack Raisanen, Kimmo J. Hatanpaa, Ashish Jindal, F. Mark Jeffrey, Changho Choi, Christopher Madden, Dana Mathews, Juan M. Pascual, Bruce E. Mickey, Craig R. Malloy, Ralph J. Deberardinis

Research output: Contribution to journalArticlepeer-review

266 Scopus citations

Abstract

Glioblastomas and brain metastases demonstrate avid uptake of 2-[18F]fluoro-2-deoxyglucose by positron emission tomography and display perturbations of intracellular metabolite pools by 1H MRS. These observations suggest that metabolic reprogramming contributes to brain tumor growth in vivo. The Warburg effect, excess metabolism of glucose to lactate in the presence of oxygen, is a hallmark of cancer cells in culture. 2-[18F]Fluoro-2-deoxyglucose-positive tumors are assumed to metabolize glucose in a similar manner, with high rates of lactate formation relative to mitochondrial glucose oxidation, but few studies have specifically examined the metabolic fates of glucose in vivo. In particular, the capacity of human brain cancers to oxidize glucose in the tricarboxylic acid cycle is unknown. Here, we studied the metabolism of human brain tumors in situ. [U-13C]Glucose (uniformly labeled glucose, i.e. d-glucose labeled with 13C in all six carbons) was infused during surgical resection, and tumor samples were subsequently subjected to 13C NMR spectroscopy. The analysis of tumor metabolites revealed lactate production, as expected. We also determined that pyruvate dehydrogenase, turnover of the tricarboxylic acid cycle, anaplerosis and de novo glutamine and glycine synthesis contributed significantly to the ultimate disposition of glucose carbon. Surprisingly, less than 50% of the acetyl-coenzyme A pool was derived from blood-borne glucose, suggesting that additional substrates contribute to tumor bioenergetics. This study illustrates a convenient approach that capitalizes on the high information content of 13C NMR spectroscopy and enables the analysis of intermediary metabolism in diverse cancers growing in their native microenvironment.

Original languageEnglish
Pages (from-to)1234-1244
Number of pages11
JournalNMR in Biomedicine
Volume25
Issue number11
DOIs
StatePublished - Nov 2012
Externally publishedYes

Keywords

  • Cancer
  • Glioblastoma
  • Glucose
  • Glutamine
  • Metabolism
  • NMR
  • Warburg effect

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