Cell
Volume 159, Issue 7, 18 December 2014, Pages 1603-1614
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Article
Acetate Is a Bioenergetic Substrate for Human Glioblastoma and Brain Metastases

https://doi.org/10.1016/j.cell.2014.11.025Get rights and content
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Highlights

  • 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

Summary

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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