Turnbull 2019 Am J Physiol Cell Physiol
|Turnbull PC, Hughes MC, Perry CGR (2019) The fatty acid derivative palmitoylcarnitine abrogates colorectal cancer cell survival by depleting glutathione. Am J Physiol Cell Physiol [Epub ahead of print].|
Abstract: Previous evidence suggests that palmitoylcarnitine incubations trigger mitochondrial-mediated apoptosis in HT29 colorectal adenocarcinoma cells, yet non-transformed cells appear resistant. The mechanism by which palmitoylcarnitine induces cancer cell death is unclear. The purpose of this investigation was to examine the relationship between mitochondrial kinetics and glutathione buffering in determining the effect of palmitoylcarnitine on cell survival. HT29 and HCT 116 colorectal adenocarcinoma cells, CCD 841 non-transformed colon cells and MCF7 breast adenocarcinoma cells were exposed to 0μM, 50μM and 100μM palmitoylcarnitine for 24-48 hours. HCT 116 and HT29 cells showed decreased cell survival following palmitoylcarnitine compared to CCD 841 cells. Palmitoylcarnitine stimulated H2O2 emission in HT29 and CCD 841 cells but increased it to a greater level in HT29 cells due largely to a higher basal H2O2 emission. This greater H2O2 emission was associated with lower glutathione buffering capacity and caspase-3 activation in HT29 cells. The glutathione depleting agent, buthionine sulfoximine, sensitized CCD 841 cells and further sensitized HT29 cells to palmitoylcarnitine-induced decreases in cell survival. MCF7 cells did not produce H2O2 when exposed to palmitoylcarnitine and were able to maintain glutathione levels. Furthermore, HT29 cells demonstrated the lowest mitochondrial oxidative kinetics vs CCD 841 and MCF7 cells. The results demonstrate that colorectal cancer is sensitive to palmitoylcarnitine due in part to an inability to prevent oxidative stress through glutathione-redox coupling thereby rendering the cells sensitive to elevations in H2O2. These findings suggest that the relationship between inherent metabolic capacities and redox regulation is altered early in response to palmitoylcarnitine.
Labels: MiParea: Respiration Pathology: Cancer
Organism: Human Tissue;cell: Endothelial;epithelial;mesothelial cell Preparation: Permeabilized cells
Regulation: Fatty acid Coupling state: LEAK, OXPHOS Pathway: N HRR: Oxygraph-2k