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

Autor:	Tiburcio PDB; Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA.; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA., Xiao B; Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA.; Department of Neurosurgery, Nanchang University Second Affiliated Hospital, Nanchang, Jiangxi, People's Republic of China., Chai Y; Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA.; Department of Neurosurgery, Nanchang University Second Affiliated Hospital, Nanchang, Jiangxi, People's Republic of China., Asper S; Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA., Tripp SR; ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah, USA., Gillespie DL; Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA., Jensen RL; Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA., Huang LE; Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA.; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2018 Oct 12; Vol. 9 (80), pp. 35100-35113. Date of Electronic Publication: 2018 Oct 12 (Print Publication: 2018).
DOI:	10.18632/oncotarget.26203
Abstrakt:	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. Competing Interests: CONFLICTS OF INTEREST The authors declare no competing interest.
Databáze:	MEDLINE
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