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Inactivation of Pyruvate Dehydrogenase Complex Mediates The Selective Effects of Butyrate on Colorectal Cancer Cells.
Author(s) -
Han Anna,
Bennett Natalie,
MacDonald Amber,
Johnstone Megan,
Whelan Jay,
Donohoe Dallas R.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.42.8
Subject(s) - butyrate , warburg effect , pyruvate dehydrogenase kinase , pyruvate dehydrogenase complex , chemistry , glycolysis , biochemistry , cancer cell , metabolism , cancer research , microbiology and biotechnology , biology , cancer , medicine , enzyme , fermentation
Butyrate, derived from the microbial fermentation of dietary fiber in the colon, is utilized as the primary energy source in the colonocyte. Butyrate can also regulate gene expression through inhibition of histone deacetylases (HDACs) in cancerous colonocytes. Butyrate has been reported to have selective effects on colorectal cancer cells where it slows cellular proliferation and induces apoptosis. Previously, we found that oxidation of butyrate is diminished in cancerous colonocytes compared to non‐cancerous colonocytes, and this difference in metabolism impacts the inhibition of HDACs by butyrate. The primary aim of this study was to characterize the mechanisms that influence butyrate oxidation in cancerous colonocytes (HCT116). We hypothesized that the decrease in butyrate oxidation observed in the cancerous colonocyte is associated with enhanced glucose uptake and utilization (the Warburg effect). Colorectal cancer cells increase glycolysis and decrease oxidative metabolism through the phosphorylation and inactivation of the pyruvate dehydrogenase complex, which pushes cellular metabolism away from the formation of acetyl‐CoA and mitochondrial respiration. We chose to target the inactivation of the pyruvate dehydrogenase complex as a major event in regulating the Warburg effect and decreasing butyrate oxidation in the colorectal cancer cell. In these experiments, the Seahorse XF 24 Analyzer was used to measure butyrate oxidation in HCT116 cells with and without dichloroacetate (DCA). DCA is a PDH kinase inhibitor that increases PDH activation. We report here that the oxidation of butyrate in colorectal cancer cells with DCA was significantly higher than those without DCA (p<0.05). Next, we tested whether the inactivation of PDH in decreasing the oxidation of butyrate was dependent upon carnitine. Towards this end, DCA did not elevate butyrate oxidation in cancerous colonocytes when carnitine was absent (p<0.05). Furthermore, inactivation of PDH was associated with decreased OCNT2 (a major carnitine transporter) and CPT1A (carnitine palmitoyltransferase 1A) expression, which both have key roles in regulating carnitine‐dependent fatty acid oxidation. These data suggest that inactivation of PDH results in decreased butyrate oxidation that is dependent upon carnitine, and provide insight into why colorectal cancer cells are sensitive to butyrate.