Glioma derived isocitrate dehydrogenase-2 mutations induced up-regulation of HIF-1α and β-catenin signaling: Possible impact on glioma cell metastasis and chemo-resistance

The identification of heterozygous mutations (with an incidence up to 85%) in either the R132 residue of isocitrate dehydrogenase-1 (IDH1) or the R172 residue of IDH2 in human low-grade diffuse gliomas was remarkable because no oncogenic pathway had been previously documented correlated with these enzymes. In spite of a recent surge in elucidating the tumorigenic activity of IDH mutations in glioblastoma, the underlying biological mechanisms remain poorly understood. We showed here that C6 glioma cells transiently over-expressing IDH2R172G induced nuclear accumulation of β-catenin, up-regulation of HIF-1α signaling and corresponding proteins expression that were closely related with tumor invasion and chemo-resistance. These results demonstrated a functional model in which IDH mutations were closely interrelated with glioma progression and could hold some therapeutic implications for future human glioma treatment.

► The links of IDH, β-catenin, HIF-1α, N-cadherin, MMPs in glioma cell were disclosed. ► IDH2R172G induced nuclear accumulation of β-catenin. ► IDH2R172G induced GSH depletion and Bcl-2 down-regulation. ► A functional model IDH2R172G played in glioma progression was proposed. ► This finding served as an important complement to existing researches on this topic.