Glioblastoma Utilizes Fatty Acids and Ketone Bodies for Growth Allowing Progression during Ketogenic Diet Therapy
Jantzen Sperry,
Michael C. Condro,
Lea Guo,
Daniel Braas,
Nathan Vanderveer-Harris,
Kristen K.O. Kim,
Whitney B. Pope,
Ajit S. Divakaruni,
Albert Lai,
Heather Christofk,
Maria G. Castro,
Pedro R. Lowenstein,
Janel E. Le Belle,
Harley I. Kornblum
Affiliations
Jantzen Sperry
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Michael C. Condro
Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, CA, USA
Lea Guo
Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, CA, USA; Department of Radiological Sciences, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Daniel Braas
UCLA Metabolomics Center, UCLA, Los Angeles, CA, USA
Nathan Vanderveer-Harris
Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, CA, USA
Kristen K.O. Kim
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Whitney B. Pope
Department of Radiological Sciences, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Ajit S. Divakaruni
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Albert Lai
Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA; Department of Neurology, UCLA, Los Angeles, CA, USA
Heather Christofk
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA; Department of Biological Chemistry, UCLA, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, USA
Maria G. Castro
Department of Neurosurgery, Department of Cell and Developmental Biology, Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Pedro R. Lowenstein
Department of Neurosurgery, Department of Cell and Developmental Biology, Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Janel E. Le Belle
Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, CA, USA
Harley I. Kornblum
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, USA; Corresponding author
Summary: 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.
