Isotopologue distributions of fatty acid oxidation inhibition in U87 glioma cells

Glioblastoma (GBM) metabolism has traditionally been characterized by a
primary dependence on aerobic glycolysis, prompting the use of the
ketogenic diet (KD) as a potential therapy. In this study we evaluated the
effectiveness of the KD in GBM and assessed the role of fatty acid
oxidation (FAO) in promoting GBM propagation. In
vitro assays revealed FA utilization throughout the GBM
metabolome, and growth inhibition in nearly every cell line in a broad
spectrum of patient-derived glioma cells treated with FAO
inhibitors. In vivo assessments revealed that knockdown
of carnitine palmitoyltransferase 1A (CPT1A), the rate limiting enzyme for
FAO, reduced the rate of tumor growth and increased survival. However, the
unrestricted ketogenic diet did not reduce tumor growth, and for some
models significantly reduced survival. Altogether, these data highlight
important roles for FA and ketone body metabolism that could serve to
improve targeted therapies in GBM.