Altered expression levels of IDH2 are involved in the development of colon cancer

Lv,Qiang; Xing,Shenyang; Li,Zhenxiao; Li,Jianhua; Gong,Pengtao; Xu,Xiaofang; Chang,Le; Jin,Xiaoxia; Gao,Feng; Li,Wei; Zhang,Guocai; Yang,Ju; Zhang,Xichen

doi:10.3892/etm.2012.676

Altered expression levels of IDH2 are involved in the development of colon cancer

Authors:
- Qiang Lv
- Shenyang Xing
- Zhenxiao Li
- Jianhua Li
- Pengtao Gong
- Xiaofang Xu
- Le Chang
- Xiaoxia Jin
- Feng Gao
- Wei Li
- Guocai Zhang
- Ju Yang
- Xichen Zhang
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Affiliations: College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062, P.R. China, The Affiliated Hospital of Jilin Medical College, Jilin 132000, P.R. China
Published online on: August 20, 2012 https://doi.org/10.3892/etm.2012.676
Pages: 801-806

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Abstract

IDH2 encodes a mitochondrial metabolic enzyme that converts isocitrate to α-ketoglutarate (α-KG) by reducing nicotinamide adenine dinucleotide phosphate (NADP+) to NADPH and participates in the citric acid cycle for energy production. Notably, this gene has been shown to be critical for cell proliferation. The abnormal expression of IDH2 has been reported in several types of cancer, and mutations in IDH2 have been identified in gliomas and acute myelogenous leukemia. The overexpression of IDH2 has been reported in endometrial, prostate and testicular cancer as well as in Kashin-Beck disease. In this study, we observed that IDH2 expression was significantly downregulated in early phase but was upregulated in advanced phase colon carcinoma compared to peritumoral tissues. In addition, we demonstrated that the growth of a colon carcinoma cell line was inhibited by IDH2-siRNA and increased following transfection with an IDH2-overexpressing plasmid. These results indicate that IDH2 may play a unique role in the development of colon carcinoma.

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1	Zhang YL, Zhang ZS, Wu BP and Zhou DY: Early diagnosis for colorectal cancer in China. World J Gastroenterol. 8:21–25. 2002.
2	Tischoff I and Tannapfel A: Epigenetic alterations in colorectal carcinomas and precancerous lesions. Z Gastroenterol. 46:1202–1206. 2008.(In German).
3	Zhang ZY and Zhao ZZ: Epidemiology of colorectal cancer and future prospects. Cancer Res Prev Treat. 27:154–156. 2000.
4	Bonnet S, Archer SL, Allalunis-Turner J, et al: A mitochondria-K⁺ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 11:37–51. 2007.PubMed/NCBI
5	Wolvetang EJ, Johnson KL, Krauer K, Ralph SJ and Linnane AW: Mitochondrial respiratory chain inhibitors induce apoptosis. FEBS Lett. 339:40–44. 1994. View Article : Google Scholar : PubMed/NCBI
6	Neuzil J, Wang XF, Dong LF, Low P and Ralph SJ: Molecular mechanism of ‘mitocan’-induced apoptosis in cancer cells epitomizes the multiple roles of reactive oxygen species and Bcl-2 family proteins. FEBS Lett. 580:5125–5129. 2006.
7	Notarnicola M, Pisanti S, Tutino V, et al: Effects of olive oil polyphenols on fatty acid synthase gene expression and activity in human colorectal cancer cells. Genes Nutr. 6:63–69. 2011. View Article : Google Scholar : PubMed/NCBI
8	Boss O, Hagen T and Lowell BB: Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. Diabetes. 49:143–156. 2000. View Article : Google Scholar : PubMed/NCBI
9	Brand MD, Affourtit C, Esteves TC, et al: Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med. 37:755–767. 2004. View Article : Google Scholar : PubMed/NCBI
10	Casteilla L, Rigoulet M and Pénicaud L: Mitochondrial ROS metabolism: modulation by uncoupling proteins. IUBMB Life. 52:181–188. 2001. View Article : Google Scholar : PubMed/NCBI
11	Horimoto M, Resnick MB, Konkin TA, et al: Expression of uncoupling protein-2 in human colon cancer. Clin Cancer Res. 10:6203–6207. 2004. View Article : Google Scholar : PubMed/NCBI
12	Kuai XY, Ji ZY and Zhang HJ: Mitochondrial uncoupling protein 2 expression in colon. World J Gastroenterol. 16:5773–5778. 2010. View Article : Google Scholar : PubMed/NCBI
13	King A, Selak MA and Gottlieb E: Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene. 25:4675–4682. 2006. View Article : Google Scholar : PubMed/NCBI
14	Yan H, Bigner DD, Velculescu V and Parsons DW: Mutant metabolic enzymes are at the origin of gliomas. Cancer Res. 69:9157–9159. 2009. View Article : Google Scholar : PubMed/NCBI
15	Geisbrecht BV and Gould SJ: The human PICD gene encodes a cytoplasmic and peroxisomal NADP⁺-dependent isocitrate dehydrogenase. J Biol Chem. 274:30527–30533. 1999. View Article : Google Scholar : PubMed/NCBI
16	Fu YJ, 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
17	Green A and Beer P: Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms. N Engl J Med. 362:369–370. 2010. View Article : Google Scholar : PubMed/NCBI
18	Reitman ZJ and Yan H: Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst. 102:932–941. 2010. View Article : Google Scholar : PubMed/NCBI
19	Ward PS, Patel J, Wise DR, et al: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 17:225–234. 2010.PubMed/NCBI
20	Kang MR, Kim MS, Oh JE, et al: Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int J Cancer. 125:353–355. 2009. View Article : Google Scholar : PubMed/NCBI
21	Sjöblom T, Jones S, Wood LD, et al: The consensus coding sequences of human breast and colorectal cancers. Science. 314:268–274. 2006.
22	Guirguis A, Elishaev E, Oh SH, Tseng GC, Zorn K and DeLoia JA: Use of gene expression profiles to stage concurrent endometrioid tumors of the endometrium and ovary. Gynecol Oncol. 108:370–376. 2008. View Article : Google Scholar : PubMed/NCBI
23	Altenberg B and Greulich KO: Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics. 84:1014–1020. 2004. View Article : Google Scholar : PubMed/NCBI
24	Wang WZ, Guo X, Duan C, et al: Comparative analysis of gene expression profiles between the normal human cartilage and the one with endemic osteoarthritis. Osteoarthritis Cartilage. 17:83–90. 2009. View Article : Google Scholar : PubMed/NCBI
25	Shin SW, Kil IS and Park JW: Silencing of mitochondrial NADP ⁺-dependent isocitrate dehydrogenase by small interfering RNA enhances heat shock-induced apoptosis. Biochem Biophys Res Commun. 366:1012–1018. 2008.PubMed/NCBI
26	Peng L, Yanjiao M, Ai-guo W, et al: A fine balance between CCNL1 and TIMP1 contributes to the development of breast cancer cells. Biochem Biophys Res Commun. 409:344–349. 2011. View Article : Google Scholar : PubMed/NCBI
27	DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S and Thompson CB: Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA. 104:19345–19350. 2007. View Article : Google Scholar
28	Berger F, Ramírez-Hernández MH and Ziegler M: The new life of a centenarian: signalling functions of NAD(P). Trends Biochem Sci. 29:111–118. 2004. View Article : Google Scholar : PubMed/NCBI
29	Belenky P, Bogan KL and Brenner C: NAD⁺ metabolism in health and disease. Trends Biochem Sci. 32:12–19. 2007.
30	Pollak N, Dölle C and Ziegler M: The power to reduce: pyridine nucleotides - small molecules with a multitude of functions. Biochem J. 402:205–218. 2007. View Article : Google Scholar : PubMed/NCBI
31	Xia Wl, Wang ZH, Wang Q, et al: Roles of NAD⁺/NADH and NADP⁺/NADPH in cell death. Curr Pharm Des. 15:12–19. 2009.
32	Ying W: NAD⁺/NADH and NAD⁺/NADH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal. 10:179–206. 2008.
33	Kim SY, Lee SM, Tak JK, Choi KS, Kwon TK and Park JW: Regulation of singlet oxygen-induced apoptosis by cytosolic NADP⁺-dependent isocitrate dehydrogenase. Mol Cell Biochem. 302:27–34. 2007. View Article : Google Scholar : PubMed/NCBI