title: Acetate is a bioenergetic substrate for human glioblastoma and brain metastases.
abstract: Glioblastomas and brain metastases are highly proliferative brain tumors with short survival times. Previously, using (13)C-NMR analysis of brain tumors resected from patients during infusion of (13)C-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-(13)C]acetate and can do so while simultaneously oxidizing [1,6-(13)C]glucose. The tumors do not oxidize [U-(13)C]glutamine. In vivo oxidation of [1,2-(13)C]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.
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Mashimo
authors.affiliation: Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Kumar
authors.initials: K
authors.lastname: Pichumani
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Vamsidhara
authors.initials: V
authors.lastname: Vemireddy
authors.affiliation: Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Kimmo J
authors.initials: KJ
authors.lastname: Hatanpaa
authors.affiliation: Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Dinesh Kumar
authors.initials: DK
authors.lastname: Singh
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Shyam
authors.initials: S
authors.lastname: Sirasanagandla
authors.affiliation: Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Suraj
authors.initials: S
authors.lastname: Nannepaga
authors.affiliation: Annette G. Strauss Center for Neuro-Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Sara G
authors.initials: SG
authors.lastname: Piccirillo
authors.affiliation: Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Kovacs
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Chan
authors.initials: C
authors.lastname: Foong
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Neurological Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Barnett
authors.affiliation: Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurological Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Mickey
authors.affiliation: Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX 75390, USA; Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Tu
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: elizabeth.maher@utsouthwestern.edu.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Maher
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: robert.bachoo@utsouthwestern.edu.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Bachoo
mesh_terms: D000106:Acetate-CoA Ligase / Q000235:genetics / Q000378:metabolism*; D000085:Acetates / Q000378:metabolism*; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D002952:Citric Acid Cycle; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology
chemical_list: D000085:Acetates; D018698:Glutamic Acid; C000595379:ACSS2 protein, human; C000595378:ACSS2 protein, mouse; D000106:Acetate-CoA Ligase