Mechanisms of non-metastatic 2 (NME2)-mediated control of metastasis across tumor types

  • Ram Krishna Thakur
  • Vinod Kumar Yadav
  • Pankaj Kumar
  • Shantanu Chowdhury
REVIEW

Abstract

Non-metastatic 23 [NM23/nucleoside diphosphate kinases (NDPK)] genes are the first discovered metastasis suppressor genes. More than two decades of research has demonstrated their roles in a variety of biological processes with NME1 and NME2 being most studied in the context of metastasis suppression. Although NME1 and NME2 share >85% homology at amino acid level, they show redundant as well as unique molecular functions. Phenotypic analyses of knockout (KO) mice for NM23 members (NDPK-A, B) and compound KO (A as well as B) showed requirement of both proteins in hematopoiesis suggesting shared functions in development disease. Several reviews have discussed NME1, however the role of NME2 appears to be relatively less understood in the context of metastasis suppression. Here, we focus on NME2 and by meta-analysis of gene expression from multiple tumor types, and survey of in vivo and vitro studies, suggest the possibility that NME2 may be one of the key factors in metastasis. This along with the relevance of normal physiological functions of NME2 in the context of metastasis is discussed. We further examined the genetic and epigenetic features of NME2 and NME1 gene promoters and found aspects of transcription control that could be unique to NME2/NME1. Findings on signaling pathways and small molecules which regulate the expression of NME2 that could be therapeutically important are also discussed.

Keywords

NM23 Meta-analysis Metastasis Transcription Metastasis suppression Regulation NME2 promoter NM23 H2 

Notes

Acknowledgments

We thank all members of SC lab for helpful discussion. Research grant from CSIR (MLP 5501), DST (Swarnajayanti Fellowship to SC), and Senior Research Fellowship to VKY (CSIR) and PK (ICMR) is acknowledged. Gene expression datasets from multiple tumor types for analysis of NME2 transcript level were obtained from expO (IGC, USA, www.intgen.org). Datasets for ChIP-seq analysis were from ENCODE consortium (http://genome.ucsc.edu/ENCODE/downloads.html).

Conflicts of interest

None.

Reference

  1. Agou F, Raveh S, Mesnildrey S, Veron M (1999) Single strand DNA specificity analysis of human nucleoside diphosphate kinase B. J Biol Chem 274:19630–19638PubMedCrossRefGoogle Scholar
  2. Aktary Z, Chapman K, Lam L, Lo A, Ji C, Graham K, Cook L, Li L, Mackey JR, Pasdar M (2010) Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1. Oncogene 29:2118–2129PubMedCrossRefGoogle Scholar
  3. Baba H, Urano T, Okada K, Furukawa K, Nakayama E, Tanaka H, Iwasaki K, Shiku H (1995) Two isotypes of murine nm23/nucleoside diphosphate kinase, nm23-M1 and nm23-M2, are involved in metastatic suppression of a murine melanoma line. Cancer Res 55:1977–1981PubMedGoogle Scholar
  4. Bai F, Feng J, Cheng Y, Shi J, Yang R, Cui H (2006) Analysis of gene expression patterns of ovarian cancer cell lines with different metastatic potentials. Int J Gynecol Cancer 16:202–209PubMedCrossRefGoogle Scholar
  5. Bhujwalla ZM, Aboagye EO, Gillies RJ, Chacko VP, Mendola CE, Backer JM (1999) Nm23-transfected MDA-MB-435 human breast carcinoma cells form tumors with altered phospholipid metabolism and pH: a 31P nuclear magnetic resonance study in vivo and in vitro. Magn Reson Med 41:897–903PubMedCrossRefGoogle Scholar
  6. Brenner AS, Thebo JS, Senagore AJ, Duepree HJ, Gramlich T, Ormsby A, Lavery IC, Fazio VW (2003) Analysis of both NM23-h1 and NM23-H2 expression identifies "at-risk" patients with colorectal cancer. Am Surg 69:203–208PubMedGoogle Scholar
  7. Caligo MA, Cipollini G, Fiore L, Calvo S, Basolo F, Collecchi P, Ciardiello F, Pepe S, Petrini M, Bevilacqua G (1995) NM23 gene expression correlates with cell growth rate and S-phase. Int J Cancer 60:837–842PubMedCrossRefGoogle Scholar
  8. Cervoni L, Egistelli L, Eufemi M, d'Abusco AS, Altieri F, Lascu I, Turano C, Giartosio A (2006) DNA sequences acting as binding sites for NM23/NDPK proteins in melanoma M14 cells. J Cell Biochem 98:421–428PubMedCrossRefGoogle Scholar
  9. Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563–572PubMedCrossRefGoogle Scholar
  10. Cheadle C, Vawter MP, Freed WJ, Becker KG (2003) Analysis of microarray data using Z score transformation. J Mol Diagn 5:73–81PubMedCrossRefGoogle Scholar
  11. Curtis CD, Likhite VS, McLeod IX, Yates JR, Nardulli AM (2007) Interaction of the tumor metastasis suppressor nonmetastatic protein 23 homologue H1 and estrogen receptor alpha alters estrogen-responsive gene expression. Cancer Res 67:10600–10607PubMedCrossRefGoogle Scholar
  12. Desvignes T, Pontarotti P, Fauvel C, Bobe J (2009) Nme protein family evolutionary history, a vertebrate perspective. BMC Evol Biol 9:256PubMedCrossRefGoogle Scholar
  13. Di L, Srivastava S, Zhdanova O, Sun Y, Li Z, Skolnik EY (2010) Nucleoside diphosphate kinase B knock-out mice have impaired activation of the K+ channel KCa3.1, resulting in defective T cell activation. J Biol Chem 285:38765–38771PubMedCrossRefGoogle Scholar
  14. D'Souza RJ, Sheikh ZA, Busund LT, Russell PJ, Crowe PJ, Yang JL (2003) Expression of nm23 protein in adult soft tissue sarcoma is correlated with histological grade. Anticancer Res 23:3289–3294PubMedGoogle Scholar
  15. Fishman JR, Gumerlock PH, Meyers FJ, Vere White RW (1994) Quantitation of NM23 expression in human prostate tissues. J Urol 152:202–207PubMedGoogle Scholar
  16. Fournier HN, Dupe-Manet S, Bouvard D, Lacombe ML, Marie C, Block MR, biges-Rizo C (2002) Integrin cytoplasmic domain-associated protein 1alpha (ICAP-1alpha ) interacts directly with the metastasis suppressor nm23-H2, and both proteins are targeted to newly formed cell adhesion sites upon integrin engagement. J Biol Chem 277:20895–20902PubMedCrossRefGoogle Scholar
  17. Fukuda M, Ishii A, Yasutomo Y, Shimada N, Ishikawa N, Hanai N, Nagata N, Irimura T, Nicolson GL, Kimura N (1996) Decreased expression of nucleoside diphosphate kinase alpha isoform, an nm23-H2 gene homolog, is associated with metastatic potential of rat mammary-adenocarcinoma cells. Int J Cancer 65:531–537PubMedCrossRefGoogle Scholar
  18. Godfried MB, Veenstra M, Sluis P, Boon K, Asperen R, Hermus MC, Schaik BD, Voute TP, Schwab M, Versteeg R, Caron HN (2002) The N-myc and c-MYC downstream pathways include the chromosome 17q genes nm23-H1 and nm23-H2. Oncogene 21:2097–2101PubMedCrossRefGoogle Scholar
  19. Hamby CV, Abbi R, Prasad N, Stauffer C, Thomson J, Mendola CE, Sidorov V, Backer JM (2000) Expression of a catalytically inactive H118Y mutant of nm23-H2 suppresses the metastatic potential of line IV Cl 1 human melanoma cells. Int J Cancer 88:547–553PubMedCrossRefGoogle Scholar
  20. Hartman J, Strom A, Gustafsson JA (2009) Estrogen receptor beta in breast cancer—diagnostic and therapeutic implications. Steroids 74:635–641PubMedCrossRefGoogle Scholar
  21. Hartsough MT, Steeg PS (2000) Nm23/nucleoside diphosphate kinase in human cancers. J Bioenerg Biomembr 32:301–308PubMedCrossRefGoogle Scholar
  22. Herak BM, Bago R, Konjevoda P, Pavelic J (2008) Gene expression profiling of Nm23-H2 overexpressing CAL 27 cells using DNA microarray. Neoplasma 55:447–454Google Scholar
  23. Hildebrandt M, Lacombe ML, Mesnildrey S, Veron M (1995) A human NDP-kinase B specifically binds single-stranded poly-pyrimidine sequences. Nucleic Acids Res 23:3858–3864PubMedCrossRefGoogle Scholar
  24. Hurtado A, Holmes KA, Ross-Innes CS, Schmidt D, Carroll JS (2011) FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nat Genet 43:27–33PubMedCrossRefGoogle Scholar
  25. Iizuka N, Mori N, Tamesa T, Tangoku A, Oka M (2003) Telomerase activity and Nm23-H2 protein expression in hepatocellular carcinoma. Anticancer Res 23:43–47PubMedGoogle Scholar
  26. Ji L, Arcinas M, Boxer LM (1995) The transcription factor, Nm23H2, binds to and activates the translocated c-myc allele in Burkitt's lymphoma. J Biol Chem 270:13392–13398PubMedGoogle Scholar
  27. Joosten M, Blazquez-Domingo M, Lindeboom F, Boulme F, Van Hoven-Beijen A, Habermann B, Lowenberg B, Beug H, Mullner EW, Delwel R, Von LM (2004) Translational control of putative protooncogene Nm23-M2 by cytokines via phosphoinositide 3-kinase signaling. J Biol Chem 279:38169–38176PubMedCrossRefGoogle Scholar
  28. Kang Y, Lee DC, Han J, Yoon S, Won M, Yeom JH, Seong MJ, Ko JJ, Lee KA, Lee K, Bae J (2007) NM23-H2 involves in negative regulation of Diva and Bcl2L10 in apoptosis signaling. Biochem Biophys Res Commun 359:76–82PubMedCrossRefGoogle Scholar
  29. Lee JS, Lee SH (2000) Cloning and characterization of cDNA encoding zebrafish Danio rerio NM23-B gene. Gene 245:75–79PubMedCrossRefGoogle Scholar
  30. Lee JH, Marshall JC, Steeg PS, Horak CE (2009a) Altered gene and protein expression by Nm23-H1 in metastasis suppression. Mol Cell Biochem 329:141–148PubMedCrossRefGoogle Scholar
  31. Lee MY, Jeong WJ, Oh JW, Choi KY (2009b) NM23H2 inhibits EGF- and Ras-induced proliferation of NIH3T3 cells by blocking the ERK pathway. Cancer Lett 275:221–226PubMedCrossRefGoogle Scholar
  32. Lu YS, Lien HC, Yeh PY, Kuo SH, Chang WC, Kuo ML, Cheng AL (2006) Glucocorticoid receptor expression in advanced non-small cell lung cancer: clinicopathological correlation and in vitro effect of glucocorticoid on cell growth and chemosensitivity. Lung Cancer 53:303–310PubMedCrossRefGoogle Scholar
  33. Marone M, Scambia G, Ferrandina G, Giannitelli C, edetti-Panici P, Iacovella S, Leone A, Mancuso S (1996) Nm23 expression in endometrial and cervical cancer: inverse correlation with lymph node involvement and myometrial invasion. Br J Cancer 74:1063–1068PubMedCrossRefGoogle Scholar
  34. Matsumura T, Suzuki T, Aizawa K, Sawaki D, Munemasa Y, Ishida J, Nagai R (2009) Regulation of transforming growth factor-beta-dependent cyclooxygenase-2 expression in fibroblasts. J Biol Chem 284:35861–35871PubMedCrossRefGoogle Scholar
  35. Matys V, Fricke E, Geffers R, Gossling E, Haubrock M, Hehl R, Hornischer K, Karas D, Kel AE, Kel-Margoulis OV, Kloos DU, Land S, Lewicki-Potapov B, Michael H, Munch R, Reuter I, Rotert S, Saxel H, Scheer M, Thiele S, Wingender E (2003) TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res 31:374–378PubMedCrossRefGoogle Scholar
  36. McDermott WG, Boissan M, Lacombe ML, Steeg PS, Horak CE (2008) Nm23-H1 homologs suppress tumor cell motility and anchorage independent growth. Clin Exp Metastasis 25:131–138PubMedCrossRefGoogle Scholar
  37. Mehta A, Orchard S (2009) Nucleoside diphosphate kinase (NDPK, NM23, AWD): recent regulatory advances in endocytosis, metastasis, psoriasis, insulin release, fetal erythroid lineage and heart failure; translational medicine exemplified. Mol Cell Biochem 329:3–15PubMedCrossRefGoogle Scholar
  38. Michelotti EF, Sanford S, Freije JM, MacDonald NJ, Steeg PS, Levens D (1997) Nm23/PuF does not directly stimulate transcription through the CT element in vivo. J Biol Chem 272:22526–22530PubMedCrossRefGoogle Scholar
  39. Miyamoto M, Iwashita S, Yamaguchi S, Ono Y (2009) Role of nm23 in the regulation of cell shape and migration via Rho family GTPase signals. Mol Cell Biochem 329:175–179PubMedCrossRefGoogle Scholar
  40. Miyazaki H, Fukuda M, Ishijima Y, Takagi Y, Iimura T, Negishi A, Hirayama R, Ishikawa N, Amagasa T, Kimura N (1999) Overexpression of nm23-H2/NDP kinase B in a human oral squamous cell carcinoma cell line results in reduced metastasis, differentiated phenotype in the metastatic site, and growth factor-independent proliferative activity in culture. Clin Cancer Res 5:4301–4307PubMedGoogle Scholar
  41. Nosaka K, Kawahara M, Masuda M, Satomi Y, Nishino H (1998) Association of nucleoside diphosphate kinase nm23-H2 with human telomeres. Biochem Biophys Res Commun 243:342–348PubMedCrossRefGoogle Scholar
  42. Ohneda K, Fukuda M, Shimada N, Ishikawa N, Ichou T, Kaji K, Toyota T, Kimura N (1994) Increased expression of nucleoside diphosphate kinases/nm23 in human diploid fibroblasts transformed by SV40 large T antigen or 60Co irradiation. FEBS Lett 348:273–277PubMedCrossRefGoogle Scholar
  43. Ouatas T, Halverson D, Steeg PS (2003a) Dexamethasone and medroxyprogesterone acetate elevate Nm23-H1 metastasis suppressor gene expression in metastatic human breast carcinoma cells: new uses for old compounds. Clin Cancer Res 9:3763–3772PubMedGoogle Scholar
  44. Ouatas T, Salerno M, Palmieri D, Steeg PS (2003b) Basic and translational advances in cancer metastasis: Nm23. J Bioenerg Biomembr 35:73–79PubMedCrossRefGoogle Scholar
  45. Postel EH, Berberich SJ, Flint SJ, Ferrone CA (1993) Human c-myc transcription factor PuF identified as nm23-H2 nucleoside diphosphate kinase, a candidate suppressor of tumor metastasis. Science 261:478–480PubMedCrossRefGoogle Scholar
  46. Postel EH, Wohlman I, Zou X, Juan T, Sun N, D'Agostin D, Cuellar M, Choi T, Notterman DA, La Perle KM (2009) Targeted deletion of Nm23/nucleoside diphosphate kinase A and B reveals their requirement for definitive erythropoiesis in the mouse embryo. Dev Dyn 238:775–787PubMedCrossRefGoogle Scholar
  47. Rayner K, Chen YX, Hibbert B, White D, Miller H, Postel EH, O'Brien ER (2007) NM23-H2, an estrogen receptor beta-associated protein, shows diminished expression with progression of atherosclerosis. Am J Physiol Regul Integr Comp Physiol 292:R743–R750PubMedCrossRefGoogle Scholar
  48. Rayner K, Chen YX, Hibbert B, White D, Miller H, Postel EH, O'Brien ER (2008) Discovery of NM23-H2 as an estrogen receptor beta-associated protein: role in estrogen-induced gene transcription and cell migration. J Steroid Biochem Mol Biol 108:72–81PubMedCrossRefGoogle Scholar
  49. Rinker-Schaeffer CW, O'Keefe JP, Welch DR, Theodorescu D (2006) Metastasis suppressor proteins: discovery, molecular mechanisms, and clinical application. Clin Cancer Res 12:3882–3889PubMedCrossRefGoogle Scholar
  50. rnaud-Dabernat S, Bourbon PM, Dierich A, Le MM, Daniel JY (2003) Knockout mice as model systems for studying nm23/NDP kinase gene functions. Application to the nm23-M1 gene. J Bioenerg Biomembr 35:19–30CrossRefGoogle Scholar
  51. Rochdi MD, Laroche G, Dupre E, Giguere P, Lebel A, Watier V, Hamelin E, Lepine MC, Dupuis G, Parent JL (2004) Nm23-H2 interacts with a G protein-coupled receptor to regulate its endocytosis through an Rac1-dependent mechanism. J Biol Chem 279:18981–18989PubMedCrossRefGoogle Scholar
  52. Sato Y, Tsuchiya B, Urao T, Baba H, Shiku H, Kodama T, Kameya T (2000) Semiquantitative immunoblot analysis of nm23-H1 and -H2 isoforms in adenocarcinomas of the lung: prognostic significance. Pathol Int 50:200–205PubMedCrossRefGoogle Scholar
  53. Schuldiner O, Shor S, Benvenisty N (2002) A computerized database-scan to identify c-MYC targets. Gene 292:91–99PubMedCrossRefGoogle Scholar
  54. Sleeman J, Steeg PS (2010) Cancer metastasis as a therapeutic target. Eur J Cancer 46:1177–1180PubMedCrossRefGoogle Scholar
  55. Srivastava S, Li Z, Ko K, Choudhury P, Albaqumi M, Johnson AK, Yan Y, Backer JM, Unutmaz D, Coetzee WA, Skolnik EY (2006) Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells. Mol Cell 24:665–675PubMedCrossRefGoogle Scholar
  56. Steeg PS, Bevilacqua G, Kopper L, Thorgeirsson UP, Talmadge JE, Liotta LA, Sobel ME (1988) Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst 80:200–204PubMedCrossRefGoogle Scholar
  57. Steeg PS, Horak CE, Miller KD (2008) Clinical-translational approaches to the Nm23-H1 metastasis suppressor. Clin Cancer Res 14:5006–5012PubMedCrossRefGoogle Scholar
  58. Syed V, Mukherjee K, Lyons-Weiler J, Lau KM, Mashima T, Tsuruo T, Ho SM (2005) Identification of ATF-3, caveolin-1, DLC-1, and NM23-H2 as putative antitumorigenic, progesterone-regulated genes for ovarian cancer cells by gene profiling. Oncogene 24:1774–1787PubMedCrossRefGoogle Scholar
  59. Takino H, Herman V, Weiss M, Melmed S (1995) Purine-binding factor (nm23) gene expression in pituitary tumors: marker of adenoma invasiveness. J Clin Endocrinol Metab 80:1733–1738PubMedCrossRefGoogle Scholar
  60. Thakur RK, Kumar P, Halder K, Verma A, Kar A, Parent JL, Basundra R, Kumar A, Chowdhury S (2009) Metastases suppressor NM23-H2 interaction with G-quadruplex DNA within c-MYC promoter nuclease hypersensitive element induces c-MYC expression. Nucleic Acids Res 37:172–183PubMedCrossRefGoogle Scholar
  61. Unoki M, Nakamura Y (2003) Methylation at CpG islands in intron 1 of EGR2 confers enhancer-like activity. FEBS Lett 554:67–72PubMedCrossRefGoogle Scholar
  62. Wei SJ, Trempus CS, Ali RC, Hansen LA, Tennant RW (2004) 12-O-tetradecanoylphorbol-13-acetate and UV radiation-induced nucleoside diphosphate protein kinase B mediates neoplastic transformation of epidermal cells. J Biol Chem 279:5993–6004PubMedCrossRefGoogle Scholar
  63. Wieland T (2007) Interaction of nucleoside diphosphate kinase B with heterotrimeric G protein betagamma dimers: consequences on G protein activation and stability. Naunyn Schmiedebergs Arch Pharmacol 374:373–383PubMedCrossRefGoogle Scholar
  64. Xiao H, Palhan V, Yang Y, Roeder RG (2000) TIP30 has an intrinsic kinase activity required for up-regulation of a subset of apoptotic genes. EMBO J 19:956–963PubMedCrossRefGoogle Scholar
  65. Yu J, Ma X, Cheung KF, Li X, Tian L, Wang S, Wu CW, Wu WK, He M, Wang M, Ng SS, Sung JJ (2010) Epigenetic inactivation of T-box transcription factor 5, a novel tumor suppressor gene, is associated with colon cancer. Oncogene 29:6464–6474PubMedCrossRefGoogle Scholar
  66. Zhang C, Lv F, Zhou L, Li X, Wu XX, Hoffman RM (2009) Effect of verapamil on the expression of EGFR and NM23 in A549 human lung cancer cells. Anticancer Res 29:27–32PubMedGoogle Scholar
  67. Zheng L, Roeder RG, Luo Y (2003) S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component. Cell 114:255–266PubMedCrossRefGoogle Scholar
  68. Zhu S, Wurdak H, Wang J, Lyssiotis CA, Peters EC, Cho CY, Wu X, Schultz PG (2009) A small molecule primes embryonic stem cells for differentiation. Cell Stem Cell 4:416–426PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ram Krishna Thakur
    • 1
  • Vinod Kumar Yadav
    • 2
  • Pankaj Kumar
    • 2
  • Shantanu Chowdhury
    • 1
    • 2
  1. 1.Proteomics and Structural Biology UnitInstitute of Genomics and Integrative Biology, CSIRDelhiIndia
  2. 2.G.N.R. Knowledge Centre for Genome InformaticsInstitute of Genomics and Integrative Biology, CSIRDelhiIndia

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