TY - JOUR
T1 - Acetate is a bioenergetic substrate for human glioblastoma and brain metastases
AU - Mashimo, Tomoyuki
AU - Pichumani, Kumar
AU - Vemireddy, Vamsidhara
AU - Hatanpaa, Kimmo J.
AU - Singh, Dinesh Kumar
AU - Sirasanagandla, Shyam
AU - Nannepaga, Suraj
AU - Piccirillo, Sara G.
AU - Kovacs, Zoltan
AU - Foong, Chan
AU - Huang, Zhiguang
AU - Barnett, Samuel
AU - Mickey, Bruce E.
AU - Deberardinis, Ralph J.
AU - Tu, Benjamin P.
AU - Maher, Elizabeth A.
AU - Bachoo, Robert M.
N1 - Funding Information:
We thank Craig Malloy and Dean Sherry for analytical assistance with the NMR spectral data, critical reading of the manuscript, and helpful discussions. We thank Sarah McNeil and Christie Sheppard for significant contributions to the patient studies, Jessica Sudderth for analyzing plasma glucose enrichment, and Dinesh Ramesh for assistance with figure preparation. This work was supported by grants from the Cancer Prevention Research Institute of Texas (RP101243 to R.J.D., E.A.M., and R.M.B.), by grants from the NIH (5R01CA154843 to E.A.M.; R01 CA157996 to R.J.D.; and 5R01NS065195 to R.M.B.), by an NIH Resource Grant (EB015908), and by a Simmons Cancer Center NIH support grant (5P30 CA142543-04). This work was also supported by philanthropic funds from The Annette G. Strauss Center for Neuro-Oncology, The Miller Family Fund in Neuro-Oncology, The Gladie Jo Salvino Fund for Glioblastoma Research at UT Southwestern Medical Center, and the Kenny Can Foundation in Dallas, Texas.
Publisher Copyright:
© 2014 Elsevier Inc. All rights reserved.
PY - 2014/12/18
Y1 - 2014/12/18
N2 - Glioblastomas and brain metastases are highly proliferative brain tumors with short survival times. Previously, using 13C-NMR analysis of brain tumors resected from patients during infusion of 13C-glucose, we demonstrated that there is robust oxidation of glucose in the citric acid cycle, yet glucose contributes less than 50% of the carbons to the acetyl-CoA pool. Here, we show that primary and metastatic mouse orthotopic brain tumors have the capacity to oxidize [1,2-13C]acetate and can do so while simultaneously oxidizing [1,6-13C]glucose. The tumors do not oxidize [U-13C]glutamine. In vivo oxidation of [1,2-13C]acetate was validated in brain tumor patients and was correlated with expression of acetyl-CoA synthetase enzyme 2, ACSS2. Together, the data demonstrate a strikingly common metabolic phenotype in diverse brain tumors that includes the ability to oxidize acetate in the citric acid cycle. This adaptation may be important for meeting the high biosynthetic and bioenergetic demands of malignant growth.
AB - Glioblastomas and brain metastases are highly proliferative brain tumors with short survival times. Previously, using 13C-NMR analysis of brain tumors resected from patients during infusion of 13C-glucose, we demonstrated that there is robust oxidation of glucose in the citric acid cycle, yet glucose contributes less than 50% of the carbons to the acetyl-CoA pool. Here, we show that primary and metastatic mouse orthotopic brain tumors have the capacity to oxidize [1,2-13C]acetate and can do so while simultaneously oxidizing [1,6-13C]glucose. The tumors do not oxidize [U-13C]glutamine. In vivo oxidation of [1,2-13C]acetate was validated in brain tumor patients and was correlated with expression of acetyl-CoA synthetase enzyme 2, ACSS2. Together, the data demonstrate a strikingly common metabolic phenotype in diverse brain tumors that includes the ability to oxidize acetate in the citric acid cycle. This adaptation may be important for meeting the high biosynthetic and bioenergetic demands of malignant growth.
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U2 - 10.1016/j.cell.2014.11.025
DO - 10.1016/j.cell.2014.11.025
M3 - Article
C2 - 25525878
AN - SCOPUS:84919903877
VL - 159
SP - 1603
EP - 1614
JO - Cell
JF - Cell
SN - 0092-8674
IS - 7
ER -