title: 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.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Isaac
authors.initials: I
authors.lastname: Marin-Valencia
authors.forename: Steve K
authors.initials: SK
authors.lastname: Cho
authors.forename: Dinesh
authors.initials: D
authors.lastname: Rakheja
authors.forename: Kimmo J
authors.initials: KJ
authors.lastname: Hatanpaa
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Mashimo
authors.forename: Ashish
authors.initials: A
authors.lastname: Jindal
authors.forename: Vamsidhara
authors.initials: V
authors.lastname: Vemireddy
authors.forename: Levi B
authors.initials: LB
authors.lastname: Good
authors.forename: Jack
authors.initials: J
authors.lastname: Raisanen
authors.forename: Xiankai
authors.initials: X
authors.lastname: Sun
authors.forename: Bruce
authors.initials: B
authors.lastname: Mickey
authors.forename: Changho
authors.initials: C
authors.lastname: Choi
authors.forename: Masaya
authors.initials: M
authors.lastname: Takahashi
authors.forename: Osamu
authors.initials: O
authors.lastname: Togao
authors.forename: Juan M
authors.initials: JM
authors.lastname: Pascual
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Deberardinis
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Maher
authors.forename: Craig R
authors.initials: CR
authors.lastname: Malloy
authors.forename: Robert M
authors.initials: RM
authors.lastname: Bachoo
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000556:secondary; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000473:pathology; D002952:Citric Acid Cycle; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000473:pathology; D019344:Lactic Acid / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D010427:Pentose Phosphate Pathway; D049268:Positron-Emission Tomography; D023041:Xenograft Model Antitumor Assays; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D019344:Lactic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D005947:Glucose