IDH1(R132H) is intrinsically tumor-suppressive but functionally attenuated by the glutamate-rich cerebral environment

Recurrent heterozygous mutation of isocitrate dehydrogenase 1 gene (IDH1), predominantly resulting in histidine substitution at arginine 132, was first identified in glioma. The biological significance of IDH1(R132H), however, has been controversial, and its prevalent association with glioma remains enigmatic. Although recent studies indicate that IDH1(R132H) is nonessential to tumor growth or even anti-tumor growth, whether IDH1(R132H) initiates gliomagenesis remains obscure. In this study, we report that IDH1(R132H) is intrinsically tumor-suppressive but the activity can be attenuated by glutamate—the cerebral neurotransmitter. We observed that IDH1(R132H) was highly suppressive of subcutaneous tumor growth driven by platelet-derived growth factor B (PDGFB), but IDH1(R132H) tumor growth and glioma penetrance were virtually indistinguishable from those of IDH1-wildtype tumors in orthotopic models. In vitro, addition of glutamate compromised IDH1(R132H) inhibition of neurosphere genesis, indicating glutamate promotion of oncogenic dominance. Furthermore, we observed that IDH1(R132H) expression was markedly decreased in tumors but became more permissible upon the deletion of tumor-suppressor gene Cdkn2a. To provide direct evidence for the opposing effect of IDH1(R132H) on PDGFB-driven glioma development, we explored tandem expression of the two molecules from a single transcript to preclude selection against IDH1(R132H) expression. Our results demonstrate that when juxtaposed with oncogenic PDGFB, IDH1(R132H) overrides the oncogenic activity and obliterates neurosphere genesis and gliomagenesis even in the glutamate-rich microenvironment. We propose therefore that IDH1(R132H) is intrinsically suppressive of glioma initiation and growth but such tumor-suppressive activity is compromised by the glutamate-rich cerebral cortex, thereby offering a unifying hypothesis for the perplexing role of IDH1(R132H) in glioma initiation and growth.