Characterization of the effects of inhibiting fatty acid beta-oxidation in Breast Cancer Cells

Student Name: 
Carl Gibson
UCD Department: 
Department of Molecular Biosciences, School of Veterinary Medicine
UCD Mentor: 
Cecilia Giulivi

Differences in the metabolism among a population of breast cancer cells leads to difficulty in fully destroying the tumor. This metabolic heterogeneity was found in glucose-specific pathways and seemed to rely on interdependence among the tumors. This study hypothesized whether cancer cells, within a single tumor, could be separated based on their oxidation of glucose over fatty acids as a fuel source. This was accomplished by utilizing MDA-231 breast adenocarcinoma cells with two different, but directed to the same target (carnitine palmitoyltransferase I or CPT-1), inhibitors of fatty acid beta-oxidation: etomoxir and 4-hydroxy-L-phenylglycine (HPG). Cells were grown for 4-5 weeks on these inhibitors to ensure selection, and then different parameters were evaluated: mitochondrial respiration, cell proliferation, metastasis, pluripotency, and differentiation. The cells that were grown in etomoxir were more metastatic than the control, but had no effect on the other aspects measured in the cells. HPG increased metastatic capacity of the cells, ATP production with octanoate, and cristae density (cytochrome c oxidase over citrate synthase activities), whereas decreased cell differentiation (as judged by ESR1). Neither etomoxir nor HPG had an effect on cell pluripotency. Neither of the treatments affected cell viability or proliferation (evaluated as doubling time). The differences between inhibitors could be due to the presence of the CPT-1b form in breast cancer cells (mainly inhibited by HPG) vs. CPT-1a which is more inhibited by etomoxir. In conclusion, breast cancer cells forced by HPG to grow on glucose oxidation tend to have more metastatic capacity and decreased differentiation, suggesting a shift towards stemness, and developed more active mitochondria, whereas etomoxir-induced glucose oxidation only led to more metastatic capacity.