Mutant Isocitrate Dehydrogenase 1 Product, 2-Hydroxy Glutarate, Activates MutT Homolog 1 in Glioma Cells via Augmentation of Reactive Oxygen Species

Abstract

MutT Homolog1 (MTH1) is an enzyme responsible for removing oxidized nucleotides from cells. Activation of MTH1 is reported in many cancer cells and is thought to be responsible for imparting resistance towards anticancer drugs. While there are several mechanisms for the activation of MTH1 in cancer cells, this study aimed to evaluate the role of mutant Isocitrate Dehydrogenase1 (mIDH1) - mediated reactive oxygen species (ROS) in the activation of MutT Homolog1 in glioma cells. MTH1 was found to be upregulated in both mIDH1 expressed and 2- HG treated cells. mIDH1 and its product, 2-HG, increased the ROS levels in the cultured glioblastoma cells. Further, increased expression and activity of MTH1 was observed in glioma tissues harboring mIDH1 compared to tissues with wild-type IDH1. Our study unveils a novel mechanism of activation of MTH1 in cells harboring mutant IDH1.