title: Cellular Metabolism and Dose Reveal Carnitine-Dependent and -Independent Mechanisms of Butyrate Oxidation in Colorectal Cancer Cells.
abstract: Dietary fiber has been suggested to suppress colorectal cancer development, although the mechanisms contributing to this beneficial effect remain elusive. Butyrate, a fermentation product of fiber, has been shown to have anti-proliferative and pro-apoptotic effects on colorectal cancer cells. The metabolic fate of butyrate in the cell is important in determining whether, it acts as an HDAC inhibitor or is consumed as a short-chain fatty acid. Non-cancerous colonocytes utilize butyrate as the primary energy source whereas cancerous colonocytes increase glucose utilization through the Warburg effect. In this study, we show that butyrate oxidation is decreased in cancerous colonocytes compared to non-cancerous colonocytes. We demonstrate that colorectal cancer cells utilize both a carnitine-dependent and carnitine-independent mechanism that contributes to butyrate oxidation. The carnitine-dependent mechanism is contingent on butyrate concentration. Knockdown of CPT1A in colorectal cancer cells abolishes butyrate oxidation. In terms of selectivity, the carnitine-dependent mechanism only regulated butyrate oxidation, as acetate and propionate oxidation were carnitine-independent. Carnitine decreased the action of butyrate as an HDAC inhibitor and suppressed induction of H3 acetylation by butyrate in colorectal cancer cells. Thus, diminished oxidation of butyrate is associated with decreased HDAC inhibition and histone acetylation. In relation to the mechanism, we find that dichloroacetate, which decreases phosphorylation of pyruvate dehydrogenase, increased butyrate oxidation and that this effect was carnitine-dependent. In conclusion, these data suggest that colorectal cancer cells decrease butyrate oxidation through inhibition of pyruvate dehydrogenase, which is carnitine-dependent, and provide insight into why butyrate shows selective effects toward colorectal cancer cells. J. Cell. Physiol. 231: 1804-1813, 2016. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee.
authors.forename: Anna
authors.initials: A
authors.lastname: Han
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee.
authors.forename: Natalie
authors.initials: N
authors.lastname: Bennett
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee.
authors.forename: Amber
authors.initials: A
authors.lastname: MacDonald
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee.
authors.forename: Megan
authors.initials: M
authors.lastname: Johnstone
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee.
authors.forename: Jay
authors.initials: J
authors.lastname: Whelan
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee.
authors.forename: Dallas R
authors.initials: DR
authors.lastname: Donohoe
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D020148:Butyric Acid / Q000378:metabolism / Q000494:pharmacology*; D002331:Carnitine / Q000378:metabolism*; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D003999:Dichloroacetic Acid / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D000074058:Solute Carrier Family 22 Member 5; D013997:Time Factors; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D027701:Organic Cation Transport Proteins; D011768:Pyruvate Dehydrogenase Complex; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D020148:Butyric Acid; D003999:Dichloroacetic Acid; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine