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

doi:10.1016/j.isci.2020.101453

Glioblastoma Utilizes Fatty Acids and Ketone Bodies for Growth Allowing Progression during Ketogenic Diet Therapy

iScience. 2020 Aug 13;23(9):101453. doi: 10.1016/j.isci.2020.101453. eCollection 2020 Sep 25.

Authors

Jantzen Sperry¹, Michael C Condro², Lea Guo^{2

3}, Daniel Braas⁴, Nathan Vanderveer-Harris², Kristen K O Kim¹, Whitney B Pope³, Ajit S Divakaruni¹, Albert Lai^{5

6}, Heather Christofk^{1

5

7

8}, Maria G Castro⁹, Pedro R Lowenstein⁹, Janel E Le Belle², Harley I Kornblum^{1

2

5

8}

Affiliations

¹ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
² Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience & Human Behavior, UCLA, Los Angeles, CA, USA.
³ Department of Radiological Sciences, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
⁴ UCLA Metabolomics Center, UCLA, Los Angeles, CA, USA.
⁵ Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.
⁶ Department of Neurology, UCLA, Los Angeles, CA, USA.
⁷ Department of Biological Chemistry, UCLA, Los Angeles, CA, USA.
⁸ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, USA.
⁹ Department of Neurosurgery, Department of Cell and Developmental Biology, Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Abstract

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.

Keywords: Cancer; Diet; Pathophysiology.

Abstract

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