Mechanisms underlying the biological changes induced by isocitrate dehydrogenase-1 mutation in glioma cells

Abstract

Isocitrate dehydrogenase 1 (IDH1) mutation has been reported to be associated with an increased overall survival in patients with glioma in a number of studies. Previous studies have focused on the mutation rate and possible metabolic pathways of the mutated IDH1 gene. However, the effects of IDH1 mutation on the biological behavior of glioma cells and the associated mechanisms, as well as the possible effects they may have on clinical therapy, have not been studied. In the present study, three eukaryotic expression vectors were constructed and transfected into the U87 cell line, specifically, a wild-type form of the IDH1 gene with the enhanced green fluorescent protein (EGFP) gene, a mutated IDH1 gene with the EGFP gene and the EGFP gene only. The three stable cell lines were selected using the G418 antibiotic. The biological behaviors of the cell lines were studied and the mechanisms underlying the biological differences between the cell lines were further investigated. The present study confirmed that IDH1 mutation induced cell cycle arrest in the G1 phase and reduced the proportion of the G2/M phase, by downregulating cell division control protein 2 homolog levels, increasing bromodomain-containing protein 2 levels and markedly limiting cell proliferation. IDH1 mutation had no effect on the apoptosis rate under routine culture conditions. Serum chemotaxis assays showed that IDH1 mutation was markedly associated with a significantly reduced invasion ability, by reducing the levels of matrix metalloproteinase (MMP)-2 and MMP-9. From this study, it may be concluded that IDH1 mutation improves prognosis in glioma patients by altering the cell cycle, inhibiting cell proliferation and downregulating cell invasion ability. The results may provide a partial explanation for the improved prognosis of patients with mutated forms of the IDH1 gene.