Imaging enzymes at work: metabolic mapping by enzyme histochemistry to study functional mechanisms of the isocitrate dehydrogenase IDH1 mutation in glioblastoma (59.3)

Abstract

Activity localization of NADP+‐ dependent isocitrate dehydrogenases (IDH) was studied quantitatively using metabolic mapping and image analysis to study the metabolic consequences of the IDH1 mutation in glioblastoma, the most aggressive form of brain tumors. The mutation is found in 70‐80% of secondary glioblastoma patients. Metabolic rewiring of cells due to the mutation causes gliomagenesis by the production of 2‐hydroxyglutarate. On the other hand, glioblastoma patients with the IDH1 mutation have a significant survival benefit of approx. one year. We found that the NADPH production capacity in glioblastoma is reduced by 38% when IDH1 is mutated (Bleeker et al. 2010). We hypothesized that this reduced production capacity of NADPH, a major metabolic involved in detoxification processes, renders glioblastoma cells less resistant against irradiation and chemotherapy and thus prolong patient survival (Baldewpersad Tewarie et al. 2013). We also demonstrated with metabolic mapping that cellular metabolism is rewired in IDH1‐mutated glioblastoma cells by elevated mitochondrial activity (Navis et al. 2013). Further metabolic mapping of human and rodent tissues showed that IDH activity is responsible for 65% of the NADPH production capacity in human brain and only for 15% in rodent brain whereas the pentose phosphate pathway was responsible for 85% of the NADPH production capacity in rodent tissues (Atai et al. 2011). It explains why the pentose phosphate pathway was always linked with cancer and not IDH because most studies on metabolism and cancer have been performed in rodents. This study clearly shows the importance of metabolic mapping as a histochemical tool to understand the consequences of a mutation in the gene of an enzyme such as IDH1.Grant Funding Source: none