Abstract
Brain tumors are exposed to ketone bodies, fatty acids, as well as lactate, carbohydrates and other substrates for energy production in mitochondria. The overwhelming majority of studies in tumor metabolism focus on conversion of glucose to lactate through glycolysis. However, there is growing evidence that cancer cells appear capable of oxidizing substrates other than glucose. Recently, we have demonstrated that acetate acts as an alternative nutrient for human gliomas and brain metastases. Glucose and acetate together contribute only up to 63% of the acetyl-CoA synthesis in brain tumors. The rest of the acetyl-CoA must be derived from other nutrients. It is well known that the normal brain uses ketone bodies as fuel. There are a few reports on using ketogenic diet as nutritional therapy to treat gliomas based on the assumption that cancer cells do not oxidize ketone bodies. We aim to investigate whether human glioblastoma cells are capable of oxidizing ketone body to meet their bioenergetic requirements. GBM cells lines derived from three patients who underwent surgical resection of the tumor at Houston Methodist Hospital were used in this study. Cells were cultured with 4.0 mM [1,2,3,4-13C]β-hydroxybutyrate (BHB) for 3 hours prior to harvesting. Snap-frozen cells were extracted and studied using 1H/13C NMR spectroscopy. [1,2,3,4-13C]BHB gets converted to [1,2-13C]acetyl-CoA in the tumor mitochondria, which enters the TCA cycle leading to 13C labeling of carbons 4 and 5 of α-ketoglutarate and glutamate during the first turn of the cycle. From 13C NMR spectrum of C4 glutamate multiplets, we determined that 9.5% ± 2.5% of [1,2-13C]acetyl-CoA was produced from BHB in the GBM cell lines used in this study. Our preliminary findings demonstrate that human GBM cell lines are fully capable of utilizing ketone bodies which contradicts to the idea behind using ketogenic diet as a therapy to treat gliomas.