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PLoS Biol. 2018 Mar 29;16(3):e2003782. doi: 10.1371/journal.pbio.2003782. eCollection 2018 Mar.

Identifying off-target effects of etomoxir reveals that carnitine palmitoyltransferase I is essential for cancer cell proliferation independent of β-oxidation.

Yao CH1,2, Liu GY1,3, Wang R1,2, Moon SH1,3, Gross RW1,3, Patti GJ1,2.

Author information

1
Department of Chemistry, Washington University, St. Louis, Missouri, United States of America.
2
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
3
Department of Internal Medicine, Division of Bioorganic and Molecular Pharmacology, Washington University School of Medicine, St. Louis, Missouri, United States of America.

Abstract

It has been suggested that some cancer cells rely upon fatty acid oxidation (FAO) for energy. Here we show that when FAO was reduced approximately 90% by pharmacological inhibition of carnitine palmitoyltransferase I (CPT1) with low concentrations of etomoxir, the proliferation rate of various cancer cells was unaffected. Efforts to pharmacologically inhibit FAO more than 90% revealed that high concentrations of etomoxir (200 μM) have an off-target effect of inhibiting complex I of the electron transport chain. Surprisingly, however, when FAO was reduced further by genetic knockdown of CPT1, the proliferation rate of these same cells decreased nearly 2-fold and could not be restored by acetate or octanoic acid supplementation. Moreover, CPT1 knockdowns had altered mitochondrial morphology and impaired mitochondrial coupling, whereas cells in which CPT1 had been approximately 90% inhibited by etomoxir did not. Lipidomic profiling of mitochondria isolated from CPT1 knockdowns showed depleted concentrations of complex structural and signaling lipids. Additionally, expression of a catalytically dead CPT1 in CPT1 knockdowns did not restore mitochondrial coupling. Taken together, these results suggest that transport of at least some long-chain fatty acids into the mitochondria by CPT1 may be required for anabolic processes that support healthy mitochondrial function and cancer cell proliferation independent of FAO.

PMID:
29596410
PMCID:
PMC5892939
DOI:
10.1371/journal.pbio.2003782
[Indexed for MEDLINE]
Free PMC Article

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