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

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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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The power to reduce: pyridine nucleotides--small molecules with a multitude of functions.

Nadine Pollak, Christian Dölle, Mathias Ziegler (2007)

The pyridine nucleotides NAD and NADP play vital roles in metabolic conversions as signal transducers and in cellular defence systems. Both coenzymes participate as electron carriers in energy transduction and biosynthetic processes. Their oxidized forms, NAD+ and NADP+, have been identified as important elements of regulatory pathways. In particular, NAD+ serves as a substrate for ADP-ribosylation reactions and for the Sir2 family of NAD+-dependent protein deacetylases as well as a precursor of the calcium mobilizing molecule cADPr (cyclic ADP-ribose). The conversions of NADP+ into the 2'-phosphorylated form of cADPr or to its nicotinic acid derivative, NAADP, also result in the formation of potent intracellular calcium-signalling agents. Perhaps, the most critical function of NADP is in the maintenance of a pool of reducing equivalents which is essential to counteract oxidative damage and for other detoxifying reactions. It is well known that the NADPH/NADP+ ratio is usually kept high, in favour of the reduced form. Research within the past few years has revealed important insights into how the NADPH pool is generated and maintained in different subcellular compartments. Moreover, tremendous progress in the molecular characterization of NAD kinases has established these enzymes as vital factors for cell survival. In the present review, we summarize recent advances in the understanding of the biosynthesis and signalling functions of NAD(P) and highlight the new insights into the molecular mechanisms of NADPH generation and their roles in cell physiology.

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Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism.

Hai Yan Gaw, Wu Hai-Yan, Zachary Reitman (2010)

Dysregulation of metabolism is a common phenomenon in cancer cells. The NADP(+)-dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) function at a crossroads of cellular metabolism in lipid synthesis, cellular defense against oxidative stress, oxidative respiration, and oxygen-sensing signal transduction. We review the normal functions of the encoded enzymes, frequent mutations of IDH1 and IDH2 recently found in human cancers, and possible roles for the mutated enzymes in human disease. IDH1 and IDH2 mutations occur frequently in some types of World Health Organization grades 2-4 gliomas and in acute myeloid leukemias with normal karyotype. IDH1 and IDH2 mutations are remarkably specific to codons that encode conserved functionally important arginines in the active site of each enzyme. To date, all IDH1 mutations have been identified at the Arg132 codon. Mutations in IDH2 have been identified at the Arg140 codon, as well as at Arg172, which is aligned with IDH1 Arg132. IDH1 and IDH2 mutations are usually heterozygous in cancer, and they appear to confer a neomorphic enzyme activity for the enzymes to catalyze the production of D-2-hydroxyglutarate. Study of alterations in these metabolic enzymes may provide insights into the metabolism of cancer cells and uncover novel avenues for development of anticancer therapeutics.

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The new life of a centenarian: signalling functions of NAD(P).

F Berger, Maria Genevive H Hernandez, Mathias Ziegler (2004)

Since the beginning of the last century, seminal discoveries have identified pyridine nucleotides as the major redox carriers in all organisms. Recent research has unravelled an unexpectedly wide array of signalling pathways that involve nicotinamide adenine dinucleotide (NAD) and its phosphorylated form, NADP. NAD serves as substrate for protein modification including protein deacetylation, and mono- and poly-ADP-ribosylation. Both NAD and NADP represent precursors of intracellular calcium-mobilizing molecules. It is now beyond doubt that NAD(P)-mediated signal transduction does not merely regulate metabolic pathways, but might hold a key position in the control of fundamental cellular processes. The comprehensive molecular characterization of NAD biosynthetic pathways over the past few years has further extended the understanding of the multiple roles of pyridine nucleotides in cell biology.

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Journal

Journal ID (nlm-ta): Exp Ther Med

Journal ID (iso-abbrev): Exp Ther Med

Journal ID (publisher-id): ETM

Title: Experimental and Therapeutic Medicine

Publisher: D.A. Spandidos

ISSN (Print): 1792-0981

ISSN (Electronic): 1792-1015

Publication date (Print): November 2012

Publication date (Electronic): 20 August 2012

Publication date PMC-release: 20 August 2012

Volume: 4

Issue: 5

Pages: 801-806

Affiliations

[1 ]College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062;

[2 ]The Affiliated Hospital of Jilin Medical College, Jilin 132000, P.R. China

Author notes

Correspondence to: Professor Jianhua Li or Professor Xichen Zhang, College of Animal Science and Veterinary Medicine, Jilin University, 5333 Xian Road, Changchun 130062, P.R. China, E-mail: jianhuali7207@ 123456163.com , E-mail: zhangxic@ 123456public.cc.jl.cn

[*]

Contributed equally

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Publisher ID: etm-04-05-0801

DOI: 10.3892/etm.2012.676

PMC ID: 3493704

PubMed ID: 23226729

SO-VID: 499a3067-33e7-44b0-8ed7-f6e736d7280b

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This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

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

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Karger: Oncology

Most cited references 22

The power to reduce: pyridine nucleotides--small molecules with a multitude of functions.

Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism.

The new life of a centenarian: signalling functions of NAD(P).

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