Mutations in isocitrate dehydrogenase 2 accelerate glioma cell migration via matrix metalloproteinase-2 and 9

Abstract

The gene encoding isocitrate dehydrogenase (IDH) is somatically mutated predominantly in secondary glioblastoma multiforme. Glioma-specific mutations in IDH1 always produced a single amino acid substitution at R132, but mutations in IDH2 were exclusively at R172 which was the analogous site to R132 in IDH1. Mutations of IDH1 and IDH2 led to simultaneous loss and gain of activities in the production of α-ketoglutarate and 2-hydroxyglutarate, respectively. Matrix metalloproteinases (MMPs) are zinc-dependent endoproteinases involved in the degradation of the extracellular matrix. The exact role of IDH2 mutant on MMPs activity and cell migration has not been fully studied. Here, we show that in response to IDH2 mutations, low levels of α-ketoglutarate increased the stabilization of HIF-1α which can contribute to tumor growth. Moreover, mutant IDH2-induced HIF-1α improved the secretion levels of pro-MMP-2 and pro-MMP-9 as well as the conversion from pro-MMP-2 to its active form, giving C6 glioma cells a higher migration potential. The HIF-1α pathway is probably a critical pathway for release of MMPs in the glioma cancer harboring IDH mutant.

Metabolism in cancer metastasis: bioenergetics, biosynthesis, and beyond

“…These include hypoxia‐inducible factor (HIF) prolyl hydroxylase domain (PHD) proteins, whose inhibition contributes to stabilization of HIF‐1α, a transcription factor responsible for many of the metabolic alterations in tumor cells . HIF‐1α stabilization increases the activity of matrix metalloproteins (MMPs), promoting ECM remodeling and metastatic cell migration . Other αKG‐dependent oxygenases include histone demethylases and ten‐eleven translocation 5‐methlycytosine hydroxylases that function in histone and DNA demethylation, respectively.…”

Enigmas of IDH mutations in hematology/oncology

“…Brain-specific expression of mutant IDH1 also caused upregulation of HIF1a and of HIF1a target gene expression in brain tissue extracts [78]. In rat C6 glioma cells, overexpression of mutant IDH2, but not wildtype IDH2, considerably stabilized HIF1a [109]. However, in the study by Koivunen et al, HIF1a protein levels were downregulated by mutant IDH1 in oligodendroglioma cells, immortalized human astrocytes, and HCT116 colorectal carcinoma cells, and the HIF1a response signature was suppressed in IDH1-mutant compared with IDH1 wildtype proneural tumors [84].…”

“…Upregulation of HIF1a in IDH-mutant glioma cells was explained by an inhibiting effect of 2HG on the EGLN enzymes [78,83,109]. However, measurement of the direct effect of R-2HG and S-2HG on EGLN1-3 consistently indicated that R-2HG was a very weak inhibitor of EGLN1 and EGLN2 and did not inhibit EGLN3 at all [84,89].…”

Glioma Cell Biology

“…Intratumoral hypoxia, a typical feature of glioblastoma microenvironment affecting multiple signaling pathways, as well as mutations of IDH (isocitrate dehydrogenase) lead to the stabilization and thereby activation of the HIF1-α subunit of the transcription factor HIF (hypoxia inducible factor), which accelerates glioma progression in part through the upregulation of MMP2, MMP9, and ADAM17 Fujiwara et al 2007;Zheng et al 2007;Fu et al 2012).…”