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

Abstract

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-(13) C(2) ]glucose. The [3-(13) C]lactate/[2,3-(13) C(2) ]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, (13) C-(13) C 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, (13) C 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 (13) C-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.

• Authors: 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
• Journal: NMR in biomedicine (NMR Biomed) Vol. 25 Issue 10 Pg. 1177-86 (Oct 2012) ISSN: 1099-1492 [Electronic] England
• PMID: 22383401 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 John Wiley & Sons, Ltd.

Chemical References

• Lactic Acid
• Glutamic Acid
• gamma-Aminobutyric Acid
• Glutamate Decarboxylase
• glutamate decarboxylase 1
• Glucose

Topics

• Animals
• Brain Neoplasms (diagnostic imaging, metabolism, secondary)
• Carcinoma, Renal Cell (enzymology, pathology)
• Citric Acid Cycle
• Disease Models, Animal
• Glioblastoma (diagnostic imaging, metabolism)
• Glucose (metabolism)
• Glutamate Decarboxylase (metabolism)
• Glutamic Acid (metabolism)
• Glycolysis
• Humans
• Kidney Neoplasms (enzymology, pathology)
• Lactic Acid (metabolism)
• Magnetic Resonance Imaging
• Mice
• Pentose Phosphate Pathway
• Positron-Emission Tomography
• Xenograft Model Antitumor Assays
• gamma-Aminobutyric Acid (metabolism)