TY - JOUR
T1 - Glucose metabolism via the pentose phosphate pathway, glycolysis and Krebs cycle in an orthotopic mouse model of human brain tumors
AU - Marin-Valencia, Isaac
AU - Cho, Steve K.
AU - Rakheja, Dinesh
AU - Hatanpaa, Kimmo J.
AU - Kapur, Payal
AU - Mashimo, Tomoyuki
AU - Jindal, Ashish
AU - Vemireddy, Vamsidhara
AU - Good, Levi B.
AU - Raisanen, Jack
AU - Sun, Xiankai
AU - Mickey, Bruce
AU - Choi, Changho
AU - Takahashi, Masaya
AU - Togao, Osamu
AU - Pascual, Juan M.
AU - Deberardinis, Ralph J.
AU - Maher, Elizabeth A.
AU - Malloy, Craig R.
AU - Bachoo, Robert M.
PY - 2012/10
Y1 - 2012/10
N2 - 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.
AB - 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.
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U2 - 10.1002/nbm.2787
DO - 10.1002/nbm.2787
M3 - Article
C2 - 22383401
AN - SCOPUS:84866303235
VL - 25
SP - 1177
EP - 1186
JO - NMR in Biomedicine
JF - NMR in Biomedicine
SN - 0952-3480
IS - 10
ER -