IDH1R132H is intrinsically tumor-suppressive but functionally attenuated by the glutamate-rich cerebral environment

Abstract

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.