title: Mutation of isocitrate dehydrogenase 1 induces glioma cell proliferation via nuclear factor-κB activation in a hypoxia-inducible factor 1-α dependent manner.
abstract: Recently, mutations of the isocitrate dehydrogenase (IDH) 1 gene, which specifically occur in the majority of low-grade and secondary high-grade gliomas, have drawn particular attention of neuro-oncologists. Mutations of the IDH1 gene have been proposed to have significant roles in the tumorigenesis, progression and prognosis of gliomas. However, the molecular mechanism of the role of IDH1 mutants in gliomagenesis remains to be elucidated. The present study, showed that forced expression of an IDH1 mutant, of which the 132th amino acid residue arginine is substituted by histidine (IDH1R132H), promoted cell proliferation in cultured cells, while wild-type IDH1 overexpression had no effect on cell proliferation. Consistent with previous studies, it was also observed that expression of hypoxia-inducible factor 1-α (HIF1-α) was upregulated in IDH1R132H expressing cells with the induction of vascular endothelial growth factor (VEGF) expression. However, knockdown of VEGF via small RNA interference had no significant influence on the cell proliferation induced by overexpression of IDH1R132H, implying that another signaling pathway may be involved. Next, forced expression of IDH1R132H was found to activate nuclear factor-κB (NF-κB), since the inhibitory IκB protein (IκBα) was highly phosphorylated and the NF-κB p65 subunit was translocated into the nucleus. Notably, knockdown of HIF1-α significantly blocked NF-κB activation, which was induced by the overexpression of IDH1 mutants. In addition, expression of IDH1 mutants markedly induced the NF-κB target gene expression, including cyclin D1 and E and c-myc, which were involved in the regulation of cell proliferation. In conclusion, it was demonstrated that the IDH1 mutant activated NF-κB in a HIF1-α‑dependent manner and was involved in the regulation of cell proliferation.
authors.affiliation: Department of Neurosurgery, General Hospital of Guangzhou Military Commanding, Guangzhou, Guangdong 510010, P.R. China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Oncology in South China, Department of Neurosurgery, Sun Yat‑Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Sai
authors.affiliation: Department of Neurosurgery, General Hospital of Guangzhou Military Commanding, Guangzhou, Guangdong 510010, P.R. China.
authors.forename: Fanghe
authors.initials: F
authors.lastname: Gong
authors.affiliation: The State Key Laboratory of Oncology in South China, Department of Neurosurgery, Sun Yat‑Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.
authors.forename: Qunying
authors.initials: Q
authors.lastname: Yang
authors.affiliation: The State Key Laboratory of Oncology in South China, Department of Neurosurgery, Sun Yat‑Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.
authors.forename: Furong
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, General Hospital of Guangzhou Military Commanding, Guangzhou, Guangdong 510010, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
mesh_terms: D021581:Active Transport, Cell Nucleus; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D019927:Cyclin E; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D016271:Proto-Oncogene Proteins c-myc; D042461:Vascular Endothelial Growth Factor A; D019938:Cyclin D1; D000072000:NF-KappaB Inhibitor alpha; D007521:Isocitrate Dehydrogenase