Home LiteratureArticle Details
PMID: 18698018 Published · ppublish English Journal Article Review

Clinical-translational approaches to the Nm23-H1 metastasis suppressor.

Clinical cancer research : an official journal of the American Association for Cancer Research ·Vol. 14 ·No. 16 ·2008-08-15 ·Pages 5006-12

Steeg PS, Horak CE, Miller KD

Abstract

Nm23-H1 significantly reduces metastasis without effects on primary tumor size and was the first discovered metastasis suppressor gene. At least three mechanisms are thought to contribute to the metastasis-suppressive effect of Nm23-H1: (a) its histidine kinase activity toward ATP-citrate lyase, aldolase C, and the kinase suppressor of ras, with the last inactivating mitogen-activated protein kinase signaling; (b) binding proteins that titer out "free" Nm23-H1 and inhibit its ability to suppress metastasis; and (c) altered gene expression downstream of Nm23-H1, particularly an inverse association with the lysophosphatidic acid receptor endothelial differentiation gene-28 (EDG2). Most metastasis suppressor genes, including Nm23-H1, affect metastatic colonization, which is the outgrowth of tumor cells in distant locations; therefore, they are of high translational interest. A phase II trial is ongoing to test the hypothesis that a compound, high-dose medroxyprogesterone acetate (MPA), used as an unconventional gluocorticoid, will stimulate breast cancer cells to reexpress Nm23-H1 and limit subsequent metastatic colonization.

MeSH Terms
Animals Antineoplastic Agents/pharmacology Clinical Trials, Phase II as Topic Humans NM23 Nucleoside Diphosphate Kinases/drug effects,physiology Neoplasm Invasiveness/genetics Neoplasms/drug therapy,enzymology Signal Transduction/drug effects,physiology
Chemicals
Antineoplastic Agents NM23 Nucleoside Diphosphate Kinases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Steeg Patricia S
Women's Cancers Section, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, 37 Convent Drive, Bethesda, MD 20892, USA. steegp@mail.nih.gov
Horak Christine E
Miller Kathy D
References (84)
84 references, click to expand
  1. Malignant effusions contain lysophosphatidic acid (LPA)-like activity.
    Ann Oncol. 1998 Apr;9(4):437-42 PMID: 9636836
  2. Expression of nm23 protein in pulmonary adenocarcinomas: inverse 1orrelation to tumor progression.
    Lung Cancer. 1997 May;17(1):103-13 PMID: 9194030
  3. Immunohistochemical expression of nm23 in primary invasive malignant melanoma is predictive of survival outcome.
    J Pathol. 2000 Feb;190(2):157-62 PMID: 10657013
  4. Adjuvant high-dose medroxyprogesterone acetate for early breast cancer: 13 years update in a multicentre randomized trial.
    Br J Cancer. 2001 Jul 6;85(1):1-8 PMID: 11437394
  5. 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. 1999 Dec;5(12):4301-7 PMID: 10632374
  6. Transfection of human nm23-H1 into the human MDA-MB-435 breast carcinoma cell line: effects on tumor metastatic potential, colonization and enzymatic activity.
    Oncogene. 1993 Sep;8(9):2325-33 PMID: 8395676
  7. NME1 protein expression and loss of heterozygosity mutations in primary human breast tumors.
    J Natl Cancer Inst. 1994 Aug 3;86(15):1167-9 PMID: 8028038
  8. Increased expression of h-prune is associated with tumor progression and poor survival in gastric cancer.
    Cancer Sci. 2007 Aug;98(8):1198-205 PMID: 17532757
  9. The human Nm23/nucleoside diphosphate kinases.
    J Bioenerg Biomembr. 2000 Jun;32(3):247-58 PMID: 11768308
  10. Reduced tumor incidence, metastatic potential, and cytokine responsiveness of nm23-transfected melanoma cells.
    Cell. 1991 Apr 5;65(1):25-35 PMID: 2013093
  11. Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women.
    J Clin Oncol. 2007 Jul 1;25(19):2798-803 PMID: 17602085
  12. Expression of the nm23 metastasis-suppressor gene product in skin tumors.
    J Cutan Pathol. 1997 Mar;24(3):151-6 PMID: 9085150
  13. Medroxyprogesterone acetate addition or substitution for tamoxifen in advanced tamoxifen-resistant breast cancer: a phase III randomized trial. Australian-New Zealand Breast Cancer Trials Group.
    J Clin Oncol. 1997 Sep;15(9):3141-8 PMID: 9294477
  14. Overexpression of h-prune in breast cancer is correlated with advanced disease status.
    Clin Cancer Res. 2005 Jan 1;11(1):199-205 PMID: 15671547
  15. The relationship between nm23, angiogenesis, and the metastatic proclivity of node-negative breast cancer.
    Cancer Res. 1998 Jul 1;58(13):2766-71 PMID: 9661889
  16. Analysis of Epstein-Barr virus reservoirs in paired blood and breast cancer primary biopsy specimens by real time PCR.
    Breast Cancer Res. 2006;8(6):R70 PMID: 17163997
  17. The effects of acetylsalicylic acid on proliferation, apoptosis, and invasion of cyclooxygenase-2 negative colon cancer cells.
    Eur J Clin Invest. 2002 Nov;32(11):838-46 PMID: 12423325
  18. Down-regulated nucleoside diphosphate kinase nm23-H1 expression is unrelated to high-risk human papillomavirus but associated with progression of cervical intraepithelial neoplasia and unfavourable prognosis in cervical cancer.
    J Clin Pathol. 2006 Oct;59(10):1044-51 PMID: 16537673
  19. ATP citrate lyase inhibition can suppress tumor cell growth.
    Cancer Cell. 2005 Oct;8(4):311-21 PMID: 16226706
  20. Fertility-preserving treatment with progestin, and pathological criteria to predict responses, in young women with endometrial cancer.
    Hum Reprod. 2007 Jul;22(7):1953-8 PMID: 17449880
  21. The effects of n-6 polyunsaturated fatty acids on the expression of nm-23 in human cancer cells.
    Br J Cancer. 1998 Mar;77(5):731-8 PMID: 9514051
  22. The metastatic suppressor Nm23-H1 interacts with EBNA3C at sequences located between the glutamine- and proline-rich domains and can cooperate in activation of transcription.
    J Virol. 2002 Sep;76(17):8702-9 PMID: 12163590
  23. Hypoxia enhances lysophosphatidic acid responsiveness in ovarian cancer cells and lysophosphatidic acid induces ovarian tumor metastasis in vivo.
    Cancer Res. 2006 Aug 15;66(16):7983-90 PMID: 16912173
  24. Mammalian histidine kinases.
    Biochim Biophys Acta. 2005 Dec 30;1754(1-2):281-90 PMID: 16188507
  25. Epstein-Barr virus nuclear protein EBNA-3C interacts with the human metastatic suppressor Nm23-H1: a molecular link to cancer metastasis.
    Nat Med. 2001 Mar;7(3):350-5 PMID: 11231635
  26. 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. 1995 May 1;55(9):1977-81 PMID: 7728768
  27. Metastasis suppressors alter the signal transduction of cancer cells.
    Nat Rev Cancer. 2003 Jan;3(1):55-63 PMID: 12509767
  28. Exposure of human breast cancer cells to the anti-inflammatory agent indomethacin alters choline phospholipid metabolites and Nm23 expression.
    Neoplasia. 2002 Sep-Oct;4(5):409-16 PMID: 12192599
  29. Effects of all-trans retinoic acid and epidermal growth factor on the expression of nm23-H1 in human hepatocarcinoma cells.
    J Cancer Res Clin Oncol. 2000 Feb;126(2):85-90 PMID: 10664247
  30. 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. 2003 Sep 1;9(10 Pt 1):3763-72 PMID: 14506169
  31. The metastasis suppressor NM23-H1 possesses 3'-5' exonuclease activity.
    J Biol Chem. 2004 Apr 23;279(17):18073-84 PMID: 14960567
  32. Evidence for a novel gene associated with low tumor metastatic potential.
    J Natl Cancer Inst. 1988 Apr 6;80(3):200-4 PMID: 3346912
  33. Nm23-H1 suppresses tumor cell motility by down-regulating the lysophosphatidic acid receptor EDG2.
    Cancer Res. 2007 Aug 1;67(15):7238-46 PMID: 17671192
  34. Tumor metastasis suppressor nm23H1 regulates Rac1 GTPase by interaction with Tiam1.
    Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4385-90 PMID: 11274357
  35. Systematic reviews of chemotherapy and endocrine therapy in metastatic breast cancer.
    Cancer Treat Rev. 2000 Jun;26(3):151-68 PMID: 10814559
  36. Inhibition of ovarian cancer metastasis by adeno-associated virus-mediated gene transfer of nm23H1 in an orthotopic implantation model.
    Cancer Gene Ther. 2006 Mar;13(3):266-72 PMID: 16179930
  37. Amplification and overexpression of PRUNE in human sarcomas and breast carcinomas-a possible mechanism for altering the nm23-H1 activity.
    Oncogene. 2001 Oct 18;20(47):6881-90 PMID: 11687967
  38. Reduced Nm23/Awd protein in tumour metastasis and aberrant Drosophila development.
    Nature. 1989 Nov 9;342(6246):177-80 PMID: 2509941
  39. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity.
    J Clin Invest. 2000 Apr;105(8):R15-24 PMID: 10772661
  40. Ki16425, a subtype-selective antagonist for EDG-family lysophosphatidic acid receptors.
    Mol Pharmacol. 2003 Oct;64(4):994-1005 PMID: 14500756
  41. MMTV-associated transcription factor binding sites increase nm23-H1 metastasis suppressor gene expression in human breast carcinoma cell lines.
    Clin Exp Metastasis. 2002;19(1):35-42 PMID: 11918081
  42. A randomized study comparing oral and standard regimens for metastatic breast cancer.
    Oncol Rep. 2001 Sep-Oct;8(5):1067-71 PMID: 11496318
  43. Elevation of breast carcinoma Nm23-H1 metastasis suppressor gene expression and reduced motility by DNA methylation inhibition.
    Cancer Res. 2001 Mar 1;61(5):2320-7 PMID: 11280805
  44. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels.
    Ann Oncol. 2002 Jan;13(1):73-80 PMID: 11863115
  45. Multiple interference of the human papillomavirus-16 E7 oncoprotein with the functional role of the metastasis suppressor Nm23-H1 protein.
    J Bioenerg Biomembr. 2006 Aug;38(3-4):215-25 PMID: 17103045
  46. Histidine kinases and histidine phosphorylated proteins in mammalian cell biology, signal transduction and cancer.
    Cancer Lett. 2003 Feb 10;190(1):1-12 PMID: 12536071
  47. 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. 2002 Jun 7;277(23):20895-902 PMID: 11919189
  48. Reduced protein expression of metastasis-related genes (nm23, KISS1, KAI1 and p53) in lymph node and liver metastases of gastric cancer.
    Int J Exp Pathol. 2007 Jun;88(3):175-83 PMID: 17504447
  49. Adjuvant chemo-hormonal therapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) with or without medroxyprogesterone acetate (MPA) for node-positive cancer patients, update at 12 years follow up.
    Breast. 2001 Feb;10(1):35-7 PMID: 14965556
  50. Differentiation of human breast carcinoma cells by a novel vitamin D analog: 1alpha-hydroxyvitamin D5.
    Int J Oncol. 2000 Jan;16(1):65-73 PMID: 10601550
  51. Phosphorylation of ATP-citrate lyase by nucleoside diphosphate kinase.
    J Biol Chem. 1995 Sep 15;270(37):21758-64 PMID: 7665595
  52. Reduced metastatic potential and c-myc overexpression of colon adenocarcinoma cells (Colon 26 line) transfected with nm23-R2/rat nucleoside diphosphate kinase alpha isoform.
    Int J Mol Med. 1998 Jul;2(1):65-8 PMID: 9854145
  53. Decreased nm23 expression, but not Ki-67 labeling index, is significantly correlated with lymph node metastasis of breast invasive ductal carcinoma.
    Int J Mol Med. 2002 Jan;9(1):25-9 PMID: 11744991
  54. Nm23-H1 metastasis suppressor expression level influences the binding properties, stability, and function of the kinase suppressor of Ras1 (KSR1) Erk scaffold in breast carcinoma cells.
    Mol Cell Biol. 2005 Feb;25(4):1379-88 PMID: 15684389
  55. Interaction of the tumor metastasis suppressor nonmetastatic protein 23 homologue H1 and estrogen receptor alpha alters estrogen-responsive gene expression.
    Cancer Res. 2007 Nov 1;67(21):10600-7 PMID: 17975005
  56. Phosphorylation of nm23-H1 by CKI induces its complex formation with h-prune and promotes cell motility.
    Oncogene. 2008 Mar 20;27(13):1853-64 PMID: 17906697
  57. Prune cAMP phosphodiesterase binds nm23-H1 and promotes cancer metastasis.
    Cancer Cell. 2004 Feb;5(2):137-49 PMID: 14998490
  58. Lysophosphatidic acid transactivates both c-Met and epidermal growth factor receptor, and induces cyclooxygenase-2 expression in human colon cancer LoVo cells.
    World J Gastroenterol. 2005 Sep 28;11(36):5638-43 PMID: 16237757
  59. Medroxyprogesterone acetate elevation of Nm23-H1 metastasis suppressor expression in hormone receptor-negative breast cancer.
    J Natl Cancer Inst. 2005 May 4;97(9):632-42 PMID: 15870434
  60. Metastasis: a therapeutic target for cancer.
    Nat Clin Pract Oncol. 2008 Apr;5(4):206-19 PMID: 18253104
  61. Expression of the antimetastatic gene nm23 in human breast cancer: an association with good prognosis.
    J Natl Cancer Inst. 1991 Feb 20;83(4):281-5 PMID: 1994057
  62. Histidine to aspartate phosphotransferase activity of nm23 proteins: phosphorylation of aldolase C on Asp-319.
    Biochem J. 2000 Mar 15;346 Pt 3:623-30 PMID: 10698688
  63. nm23 protein expression in colorectal carcinoma metastasis in regional lymph nodes and the liver.
    Eur J Surg Oncol. 2001 Mar;27(2):170-4 PMID: 11289754
  64. Histone acetylation and gastrointestinal carcinogenesis.
    Ann N Y Acad Sci. 2003 Mar;983:220-31 PMID: 12724227
  65. Increased lipogenesis in cancer cells: new players, novel targets.
    Curr Opin Clin Nutr Metab Care. 2006 Jul;9(4):358-65 PMID: 16778563
  66. Increased lung metastasis in transgenic NM23-Null/SV40 mice with hepatocellular carcinoma.
    J Natl Cancer Inst. 2005 Jun 1;97(11):836-45 PMID: 15928304
  67. Evidence for interaction between human PRUNE and nm23-H1 NDPKinase.
    Oncogene. 1999 Dec 2;18(51):7244-52 PMID: 10602478
  68. 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. 1996 Feb 8;65(4):531-7 PMID: 8621239
  69. Prognostic significance of nm23-H1 expression in oral squamous cell carcinoma.
    Br J Cancer. 2004 Jun 1;90(11):2186-93 PMID: 15150613
  70. Epstein-Barr virus, beta-catenin, and E-cadherin in gastric carcinomas.
    J Korean Med Sci. 2007 Oct;22(5):855-61 PMID: 17982235
  71. NM23-H1 tumor suppressor physically interacts with serine-threonine kinase receptor-associated protein, a transforming growth factor-beta (TGF-beta) receptor-interacting protein, and negatively regulates TGF-beta signaling.
    J Biol Chem. 2007 Apr 20;282(16):12075-96 PMID: 17314099
  72. Nm23-H1 suppresses metastasis by inhibiting expression of the lysophosphatidic acid receptor EDG2.
    Cancer Res. 2007 Dec 15;67(24):11751-9 PMID: 18089805
  73. Enhanced malignant progression of nasopharyngeal carcinoma cells mediated by the expression of Epstein-Barr nuclear antigen 1 in vivo.
    J Pathol. 1996 Nov;180(3):243-8 PMID: 8958799
  74. Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor.
    Cell. 2003 Mar 7;112(5):659-72 PMID: 12628186
  75. Dissociative glucocorticoid activity of medroxyprogesterone acetate in normal human lymphocytes.
    J Clin Endocrinol Metab. 1999 Nov;84(11):4055-61 PMID: 10566649
  76. nm23 in ovarian cancer: correlation with clinical outcome and other clinicopathologic and biochemical prognostic parameters.
    J Clin Oncol. 1996 Feb;14(2):334-42 PMID: 8636741
  77. Transfection of the nm23-H1 gene into human hepatocarcinoma cell line inhibits the expression of sialyl Lewis X, alpha1,3 fucosyltransferase VII, and metastatic potential.
    J Cancer Res Clin Oncol. 2002 Apr;128(4):189-96 PMID: 11935309
  78. Epstein-Barr virus latent nuclear antigens can induce metastasis in a nude mouse model.
    J Virol. 2007 Oct;81(19):10352-61 PMID: 17634231
  79. Effects of cytokine-mediated modulation of nm23 expression on the invasion and metastatic behavior of B16F10 melanoma cells.
    Int J Cancer. 1995 Jan 17;60(2):204-10 PMID: 7829217
  80. Aldolase C-positive cerebellar Purkinje cells are resistant to delayed death after cerebral trauma and AMPA-mediated excitotoxicity.
    Eur J Neurosci. 2007 Aug;26(3):649-56 PMID: 17686042
  81. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer.
    Cancer Res. 2000 Apr 1;60(7):1878-86 PMID: 10766175
  82. nm23 as a prognostic marker in primary cutaneous melanoma: evaluation using tissue microarray in a patient group with long-term follow-up.
    Melanoma Res. 2005 Oct;15(5):435-40 PMID: 16179871
  83. The type 1 lysophosphatidic acid receptor is a target for therapy in bone metastases.
    Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9643-8 PMID: 16769891
  84. Nm23-H1 metastasis suppressor phosphorylation of kinase suppressor of Ras via a histidine protein kinase pathway.
    J Biol Chem. 2002 Aug 30;277(35):32389-99 PMID: 12105213
Article Info
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
Abbr.
Clin Cancer Res
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-08-0238
Email
steegp@mail.nih.gov
Published
2008-08-15
Pages
5006-12
Language
English
Region
United States
NLM ID
9502500
PMCID
PMC2730725
Subset
IM
Grants
Intramural NIH HHS · Z01 SC000892-24 · United States
External Links
PubMed source DOI: 10.1158/1078-0432.CCR-08-0238 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2