Overexpression of isocitrate dehydrogenase-1R132H enhances the proliferation of A172 glioma cells via aerobic glycolysis

Nie,Quanmin; Guo,Pin; Guo,Liemei; Lan,Jin; Lin,Yingying; Guo,Fang; Zhou,Sunhai; Ge,Jianwei; Mao,Qing; Li,Xiaoxiong; Qiu,Yongming

doi:10.3892/mmr.2015.3187

Overexpression of isocitrate dehydrogenase-1R132H enhances the proliferation of A172 glioma cells via aerobic glycolysis

Authors:
- Quanmin Nie
- Pin Guo
- Liemei Guo
- Jin Lan
- Yingying Lin
- Fang Guo
- Sunhai Zhou
- Jianwei Ge
- Qing Mao
- Xiaoxiong Li
- Yongming Qiu
View Affiliations

Affiliations: Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China, Shanghai Institute of Head Trauma, Shanghai 200127, P.R. China, Laboratory of Targeted Tumor Therapy, Key Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, P.R. China
Published online on: January 13, 2015 https://doi.org/10.3892/mmr.2015.3187
Pages: 3715-3721

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Gliomas are the most common type of primary malignancy of the central nervous system. The identification of mutations in the gene encoding isocitrate dehydrogenase‑1 (IDH1) represents a key area of investigation in studies on glioma. The IDH1R132H mutation is a heterozygous point mutation, which affects the amino acid arginine at position 132, however, the metabolic importance of this mutation in tumor cell growth remains to be elucidated. In the present study, A172 glioma cell lines stably overexpressing either wild‑type IDH1 or IDH1R132H were produced. The results demonstrated that the IDH1R132H mutation enhanced the proliferation of the A172 glioma cells in vitro. Furthermore, IDH1R132H performed this function by elevating the expression levels of hypoxia inducible factor‑1α, leading to an increase in the expression levels of the key glycolytic enzymes, glucose transporter 1 and hexokinase 2. Therefore, the metabolism was shifted towards aerobic glycolysis, leading to an increase in glucose uptake and lactate production. These findings demonstrated that the IDH1R132H molecular target was involved in orchestrating the Warburg effect in mutant IDH1R132H glioma cells.

View Figures

View References

1	Louis DN, Ohgaki H, Wiestler OD, et al: The 2007 WHO classification of tumours of the central nervous system. Acta Neurophathol. 114:97–109. 2007. View Article : Google Scholar
2	Warburg O: On the origin of cancer cells. Science. 123:309–314. 1956. View Article : Google Scholar : PubMed/NCBI
3	Jang M, Kim SS and Lee J: Cancer cell metabolism: implications for therapeutic targets. Exp Mol Med. 45:e452013. View Article : Google Scholar : PubMed/NCBI
4	Dang L, Jin S and Su SM: IDH mutations in glioma and acute myeloid leukemia. Trends Mol Med. 16:387–397. 2010. View Article : Google Scholar : PubMed/NCBI
5	Fu Y, Huang R, Du J, Yang R, An N and Liang A: Glioma-derived mutations in IDH: from mechanism to potential therapy. Biochem Biophys Res Commun. 397:127–130. 2010. View Article : Google Scholar : PubMed/NCBI
6	Borodovsky A, Seltzer MJ and Riggins GJ: Altered cancer cell metabolism in gliomas with mutant IDH1 or IDH2. Curr Opin Oncol. 24:83–89. 2012. View Article : Google Scholar
7	Yan H, Parsons DW, Jin G, et al: IDH1 and IDH2 mutations in gliomas. N Engl J Med. 360:765–773. 2009. View Article : Google Scholar : PubMed/NCBI
8	Turcan S, Rohle D, Goenka A, et al: IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 483:479–483. 2012. View Article : Google Scholar : PubMed/NCBI
9	Kloosterhof NK, Bralten LB, Dubbink HJ, French PJ and van den Bent MJ: Isocitrate dehydrogenase-1 mutations: a fundamentally new understanding of diffuse glioma? Lancet Oncol. 12:83–91. 2011. View Article : Google Scholar
10	Gravendeel LA, Kloosterhof NK, Bralten LB, et al: Segregation of non-p.R132H mutations in IDH1 in distinct molecular subtypes of glioma. Hum Mutat. 31:E1186–E1199. 2010. View Article : Google Scholar : PubMed/NCBI
11	Zhao S, Lin Y, Xu W, et al: Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 324:261–265. 2009. View Article : Google Scholar : PubMed/NCBI
12	Xu W, Yang H, Liu Y, et al: Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 19:17–30. 2011. View Article : Google Scholar : PubMed/NCBI
13	Sanson M, Marie Y, Paris S, et al: Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol. 27:4150–4154. 2009. View Article : Google Scholar : PubMed/NCBI
14	Houillier C, Wang X, Kaloshi G, et al: IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology. 75:1560–1566. 2010. View Article : Google Scholar : PubMed/NCBI
15	Li S, Chou AP, Chen W, et al: Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation. Neuro Oncol. 15:57–68. 2013. View Article : Google Scholar :
16	Elstrom RL, Bauer DE, Buzzai M, et al: Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 64:3892–3899. 2004. View Article : Google Scholar : PubMed/NCBI
17	Mobasheri A, Richardson S, Mobasheri R, Shakibaei M and Hoyland JA: Hypoxia inducible factor-1 and facilitative glucose transporters GLUT1 and GLUT3: putative molecular components of the oxygen and glucose sensing apparatus in articular chondrocytes. Histol Histopathol. 20:1327–1338. 2005.PubMed/NCBI
18	Wolf A, Agnihotri S, Micallef J, et al: Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J Exp Med. 208:313–326. 2011. View Article : Google Scholar : PubMed/NCBI
19	Mueckler M, Caruso C, Baldwin SA, et al: Sequence and structure of a human glucose transporter. Science. 229:941–945. 1985. View Article : Google Scholar : PubMed/NCBI
20	Liu H, Hu YP, Savaraj N, Priebe W and Lampidis TJ: Hypersensitization of tumor cells to glycolytic inhibitors. Biochemistry. 40:5542–5547. 2001. View Article : Google Scholar : PubMed/NCBI
21	Chun YS, Yeo EJ, Choi E, et al: Inhibitory effect of YC-1 on the hypoxic induction of erythropoietin and vascular endothelial growth factor in Hep3B cells. Biochem Pharmacol. 61:947–954. 2001. View Article : Google Scholar : PubMed/NCBI
22	Zhu J, Cui G, Chen M, et al: Expression of R132H mutational IDH1 in human U87 glioblastoma cells affects the SREBP1a pathway and induces cellular proliferation. J Mol Neurosci. 50:165–171. 2013. View Article : Google Scholar
23	Bralten LB, Kloosterhof NK, Balvers R, et al: IDH1 R132H decreases proliferation of glioma cell lines in vitro and in vivo. Ann Neurol. 69:455–463. 2011. View Article : Google Scholar : PubMed/NCBI
24	Griguer CE, Oliva CR and Gillespie GY: Glucose metabolism heterogeneity in human and mouse malignant glioma cell lines. J Neurooncol. 74:123–133. 2005. View Article : Google Scholar : PubMed/NCBI
25	Lunt SY and Vander Heiden MG: Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 27:441–464. 2011. View Article : Google Scholar : PubMed/NCBI
26	Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI
27	Marin-Hernandez A, Gallardo-Perez JC, Ralph SJ, Rodriguez-Enriquez S and Moreno-Sanchez R: HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms. Mini Rev Med Chem. 9:1084–1101. 2009. View Article : Google Scholar : PubMed/NCBI
28	Finley LW, Carracedo A, Lee J, et al: SIRT3 opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization. Cancer Cell. 19:416–428. 2011. View Article : Google Scholar : PubMed/NCBI
29	Dang CV, Le A and Gao P: MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res. 15:6479–6483. 2009. View Article : Google Scholar : PubMed/NCBI
30	Mathupala SP, Rempel A and Pedersen PL: Glucose catabolism in cancer cells: identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J Biol Chem. 276:43407–43412. 2001. View Article : Google Scholar : PubMed/NCBI