ABSTRACT
Glioblastoma (GBM) metabolism has traditionally been characterized by a dependence on aerobic glycolysis, prompting use of the ketogenic diet as a potential therapy. We observed growth-promoting effects on U87 GBM of both ketone body and fatty acid (FA) supplementation under physiological glucose conditions. An in vivo assessment of the unrestricted ketogenic diet surprisingly resulted in increased tumor growth and decreased animal survival. These effects are abrogated by FAO inhibition using knockdown of carnitine palmitoyltransferase 1 (CPT1). Primary patient GBM cultures revealed significant utilization of FAO regardless of tumorigenic mutational status and decreased proliferation, increased apoptosis, and elevated mitochondrial ROS production with CPT1 inhibition. Metabolomic tracing with 13C-labeled fatty acids showed significant FA utilization within the TCA cycle, indicating that FAO is used for both bioenergetics and production of key intermediates. These data demonstrate important roles for FA and ketone body metabolism that could serve to improve targeted therapies in GBM.
Footnotes
Financial Support: This work was supported in whole or part by National Institute of Health (NIH) Grants: NS052563 (H.I.K.) and CA179071 (A.L.) the UCLA SPORE in Brain Cancer (P50 CA211015); and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (H.I.K.)
Conflicts of Interest: The authors disclose no potential conflicts of interest.