CBMT-11. PEROXISOMAL FATTY ACID OXIDATION IN GLIOBLASTOMA DURING HYPOXIA

BACKGROUND: Peroxisomal fatty acid oxidation (FAO) offers some unique metabolic advantages compared to mitochondrial FAO that may be important to cancer cells adapting to chronic hypoxia exacerbated by anti-angiogenic treatment. When peroxisomal FAO is dominant, the resulting low FADH(2)/NADH ratio allows for more efficient oxygen utilization and lower oxidative stress production during oxidative phosphorylation. Our previous findings suggest cells from tumors treated with bevacizumab are more sensitive to peroxisomal FAO inhibition. The current study further examines changes in peroxisomes, mitochondria, and their FAO pathways, and their roles in adaptation to hypoxia and anti-angiogenic treatment. METHODS: Peroxisomal number was determined by electron microscopy. Gene expression was determined by QT-PCR. RESULTS: Metabolomic analysis by NMR/MRS revealed glioblastoma cells under chronic hypoxia (2–5 weeks) likely utilize less mitochondrial FAO and showed signs of increased oxidative stress. In some cell lines we observed that chronic hypoxic cells were more sensitive to treatment with a peroxisomal FAO inhibitor, particularly in an anti-angiogenic resistant tumor cell line. Increased expression (RQ>2) of the genes ACADVL, ACADS, and DECR2, suggests an increase in mitochondrial FAO for very long and short fatty acids and increase in peroxisomal FAO for unsaturated fatty acids. There were higher overall levels of peroxisomes in the anti-angiogenic resistant tumor cell line and lower levels of mitochondria in hypoxia compared to normoxia for cell lines which were sensitive to peroxisomal FAO inhibition (p