Acetate Is a Bioenergetic Substrate for Human Glioblastoma and Brain Metastases

• Published in: Cell Vol. 159; no. 7; pp. 1603 - 1614
• Main Authors: Mashimo, Tomoyuki, Pichumani, Kumar, Vemireddy, Vamsidhara, Hatanpaa, Kimmo J., Singh, Dinesh Kumar, Sirasanagandla, Shyam, Nannepaga, Suraj, Piccirillo, Sara G., Kovacs, Zoltan, Foong, Chan, Huang, Zhiguang, Barnett, Samuel, Mickey, Bruce E., DeBerardinis, Ralph J., Tu, Benjamin P., Maher, Elizabeth A., Bachoo, Robert M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.12.2014
• Subjects: acetate-CoA ligase; Acetate-CoA Ligase - genetics; Acetate-CoA Ligase - metabolism; acetates; Acetates - metabolism; acetyl coenzyme A; Animals; brain; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - secondary; Citric Acid Cycle; Disease Models, Animal; Glioblastoma - metabolism; Glioblastoma - pathology; glucose; Glutamic Acid - metabolism; glutamine; Humans; metastasis; Mice; Neoplasm Metastasis - pathology; neoplasms; oxidation; patients; phenotype; tricarboxylic acid cycle
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2014.11.025

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. [Display omitted] •13C-acetate can be oxidized by glioblastoma human orthotopic models in vivo•A wide range of brain metastasis orthotopic models can oxidize 13C-acetate in vivo•13C-acetate infused in patients is oxidized by glioblastoma and brain metastases•Acetyl-CoA synthetase 2 is highly expressed in human brain tumors Oxidation of acetate into the Krebs cycle occurs in primary and metastatic tumors in vivo, indicating acetate as a widespread bioenergetic substrate for cancer progression.