Glucose metabolism via the pentose phosphate pathway, glycolysis and Krebs cycle in an orthotopic mouse model of human brain tumors

Isaac Marin-Valencia, Steve K. Cho, Dinesh Rakheja, Kimmo J. Hatanpaa, Payal Kapur, Tomoyuki Mashimo, Ashish Jindal, Vamsidhara Vemireddy, Levi B. Good, Jack Raisanen, Xiankai Sun, Bruce Mickey, Changho Choi, Masaya Takahashi, Osamu Togao, Juan M. Pascual, Ralph J. Deberardinis, Elizabeth A. Maher, Craig R. Malloy, Robert M. Bachoo

Research output: Contribution to journalArticlepeer-review

63 Scopus citations


It has been hypothesized that increased flux through the pentose phosphate pathway (PPP) is required to support the metabolic demands of rapid malignant cell growth. Using orthotopic mouse models of human glioblastoma (GBM) and renal cell carcinoma metastatic to brain, we estimated the activity of the PPP relative to glycolysis by infusing [1,2-13C2]glucose. The [3-13C]lactate/[2,3-13C2]lactate ratio was similar for both the GBM and brain metastasis and their respective surrounding brains (GBM, 0.197±0.011 and 0.195±0.033, respectively (p=1); metastasis: 0.126 and 0.119±0.033, respectively). This suggests that the rate of glycolysis is significantly greater than the PPP flux in these tumors, and that the PPP flux into the lactate pool is similar in both tumors. Remarkably, 13C-13C coupling was observed in molecules derived from Krebs cycle intermediates in both tumor types, denoting glucose oxidation. In the renal cell carcinoma, in contrast with GBM, 13C multiplets of γ-aminobutyric acid (GABA) differed from its precursor glutamate, suggesting that GABA did not derive from a common glutamate precursor pool. In addition, the orthotopic renal tumor, the patient's primary renal mass and brain metastasis were all strongly immunopositive for the 67-kDa isoform of glutamate decarboxylase, as were 84% of tumors on a renal cell carcinoma tissue microarray of the same histology, suggesting that GABA synthesis is cell autonomous in at least a subset of renal cell carcinomas. Taken together, these data demonstrate that 13C-labeled glucose can be used in orthotopic mouse models to study tumor metabolism in vivo and to ascertain new metabolic targets for cancer diagnosis and therapy.

Original languageEnglish
Pages (from-to)1177-1186
Number of pages10
JournalNMR in Biomedicine
Issue number10
StatePublished - Oct 2012
Externally publishedYes


  • Brain
  • C NMR
  • Glioblastoma
  • Intermediary metabolism
  • Mouse model
  • Renal cell carcinoma


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