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CBMT-01. ALANINE FUELS ENERGY METABOLISM OF GLIOBLASTOMA CELLS


 Despite available aggressive treatment options, glioblastoma multiforme (GBM) has a median survival of 16 months indicating an urgent unmet need to develop new therapeutic strategies. Earlier, we have demonstrated that both glucose and acetate are the two major nutrients leading to synthesis of approximately ~60% acetyl-CoA in the brain tumors. Therefore, there must be other nutrients that may contribute to bioenergetic needs of highly proliferative GBM cells. Alanine is one of the non-essential amino acids (NEAA) that is constantly produced in cancer cells through Warburg glycolysis and its role in cancer metabolism is not well understood. Recently, it has been shown that alanine produced by pancreatic stellar cells contributed to the energy metabolism in pancreatic cancer cells. However, it is not known whether GBM can use alanine as an energy source. Here, we test whether GBM cells have the ability to metabolize alanine as a fuel to meet its increased energy requirements. Patient-derived GBM cells were cultured with 2.0 mM [3-13C]alanine for the final 24 hours, harvested in 50% methanol, snap-frozen in liquid N2, freeze-thaw cycle 3 times and lysates were stored at -80 °C. Derivatized material from the frozen lysates were used for GC-MS analysis to determine carbon mass isotopomer distribution (MID) of various glycolytic and TCA cycle intermediates. Our results indicated that [3-13C]alanine entered the GBM cells and produced [3-13C]lactate via pyruvate. Also, alanine-derived [3-13C]pyruvate led to the generation of [2-13C]acetyl-CoA, which entered TCA cycle and produced M+1 13C isotopomers of citrate, glutamate, malate and aspartate. MID showed the following 13C enrichment (M+1) values: citrate, 6.9 % ± 0.3%; glutamate, 4.4% ± 0.3%; malate, 2.1% ± 0.6%; 2.1% ± 0.5%. This preliminary data shows that GBM cells are capable of utilizing alanine to generate energy and produce precursors for biomolecular synthesis.