Abstract 4971: The oncometabolite (R)-2-hydroxyglutarate modulates stress-induced caspase activity in glioma cells

Abstract

Abstract Point mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are present in the majority of WHO grade II and III gliomas, as well as secondary grade IV glioblastomas. These are gain-of-function mutations resulting in the neoenzymatic conversion of alpha-ketoglutarate into R-2-hydroxyglutarate (2HG), which is present in high concentrations (10-30 mM) in mutated gliomas. The mutation appears to be a favorable prognostic marker, suggesting better response to stressors like adjuvant radiation and chemotherapy; however, its effects on cell signaling and glioma cell death are not fully understood. In this study we investigated the impact of 2HG in glioma cell survival pathways. A single pulse of 2HG (30mM) increased phosphorylated Erk (p-Erk 1/2), but not pAkt, in the PTEN-intact glioma cell lines LN18 and LN229. Both p-Erk 1/2 and pAkt were unchanged in the PTEN-deficient cell lines U87 and U138. A single 2HG pulse, followed by prolonged withholding of medium changes, also enhanced caspase 3/7 activity in LN18 cells and LN229 cells, whereas it actually suppressed caspase 3/7 activity in U87 and U138 cells. Pretreatment with the MEK inhibitor UO126 prior to the 2HG pulse suppressed caspase 3/7 activity in LN18 cells, but not in LN229 cells. In U87 cells, the 2HG-induced suppression of caspase 3/7 activity was reversed by UO126, while no change was observed in U138 cells. These data indicate that 2HG can modulate stress-induced cell death in a MAPK/ERK-dependent manner, but that such modulation may vary greatly depending on the occurrence of other genetic aberrations in gliomas. Ongoing studies are pursuing potential mechanisms via which 2HG exerts such functionally divergent effects, aiming to develop better adjuvant therapeutic approaches for IDH-mutant gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4971. doi:1538-7445.AM2012-4971</jats:p