Journal of Bioenergetics and Biomembranes

, Volume 35, Issue 1, pp 73–79 | Cite as

Basic and Translational Advances in Cancer Metastasis: Nm23

  • Taoufik OuatasEmail author
  • Massimiliano Salerno
  • Diane Palmieri
  • Patricia S. Steeg


Cancer metastasis is a significant contributor to breast cancer patient morbidity and mortality. To develop new anti-metastatic therapies, we need to understand the biological and biochemical mechanisms of metastasis. Toward these efforts, we and others have studied metastasis suppressor genes, which halt metastasis in vivo without affecting primary tumor growth. The first metastasis suppressor gene confirmed was nm23, also known as NDP kinase. Using in vitro assays, nm23 overexpression resulted in reduced anchorage-independent colonization in response to TGF-β, reduced invasion and motility in response to multiple factors, and increased differentiation. We hypothesize that the mechanism of action of Nm23 in metastasis suppression involves diminished signal transduction, downstream of a particular receptor. We hypothesize that a histidine protein kinase activity of Nm23 underlies its suppression of metastasis, and identify candidate substrates. This review also discusses therapeutic options on the basis of reexpression of metastasis suppressors.

Nm23 metastasis suppressor breast 


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  1. Baba, H., Urano, T., Okada, K., Furukawa, K., Nakayama, E., Tanaka, H., Iwasaki, K., and Shiku, H. (1995). Cancer Res. 55, 1977-1981.PubMedGoogle Scholar
  2. Bell, B., Xing, H., Yan, K., Gautam, N., and Muslin, A. (1999). J. Biol. Chem. 274, 7982-7986.PubMedGoogle Scholar
  3. Bhujwalla, Z., Aboagye, E., Gilles, R., Chack, V., Mendola, C., and Backer, J. (1999). Magn. Reson. Med. 41, 897-903.PubMedGoogle Scholar
  4. Cacace, A., Michaud, N., Therrien, M., Mathes, K., Copeland, T., Rubin, G., and Morrison, D. (1999). Mol. Cell. Biol. 19, 229-240.PubMedGoogle Scholar
  5. Chambers, A., Groom, A., and MacDonald, I. (2002). Nat. Cancer Rev. 2, 563-572.Google Scholar
  6. Chang, C., Zhu, X.-X., Thoraval, D., Ungar, D., Rawwas, J., Hora, N., Strahler, J., Hanash, S., and Radany, E. (1994). Nature 370, 335-336.PubMedGoogle Scholar
  7. Cho, S., Lee, N., Jung, Y., Lee, H., Lee, K., Kim, E., and Chae, S. (2001). Biochem. Biophys. Res. Comm. 289, 738-743.PubMedGoogle Scholar
  8. Denouel-Galy, A., Douville, E., Warne, P., Papin, C., Laugier, D., Calothy, G., Downward, J., and Eychene, A. (1997). Curr. Biol. 8, 46-55.Google Scholar
  9. Engel, M., Veron, M., Theisinger, B., Lacombe, M.-L., Seib, T., Dooley, S., and Welter, C. (1995). Eur. J. Biochem. 234, 200-207.PubMedGoogle Scholar
  10. Ferguson, A., Flatow, U., MacDonald, N., Larminant, F., Bohr, V., and Steeg, P. (1996). Cancer Res. 56, 2931-2935.PubMedGoogle Scholar
  11. Freije, J. M. P., Blay, P., MacDonald, N. J., Manrow, R. E., and Steeg, P. S. (1997). J. Biol. Chem. 272, 5525-5532.PubMedGoogle Scholar
  12. Fukuda, M., Ishii, A., Yasutomo, Y., Shimada, N., Ishikawa, N., Hanai, N., Nagara, N., Irimura, T., Nicolson, G., and Kimura, N. (1996). Int. J. Cancer 65, 531-537.PubMedGoogle Scholar
  13. Hartsough, M., Clare, S., Mair, M., Elkahloun, A., Sgroi, D., Osborne, C., Clark, G., and Steeg, P. (2001). Cancer Res. 61, 2320-2327.PubMedGoogle Scholar
  14. Hartsough, M., Morrison, D., Salerno, M., Palmieri, D., Ouatas, T., Mair, M., Patrick, J., and Steeg, P. (2002). J. Biol. Chem. 277, 32389-32399.PubMedGoogle Scholar
  15. Hartsough, M., and Steeg, P. (2000). J. Bioenerg. Biomembr. 32, 301-308.PubMedGoogle Scholar
  16. Heimann, R., Ferguson, D., and Hellman, S. (1998). Cancer Res. 58, 2766-2771.PubMedGoogle Scholar
  17. Heimann, R., and Hellman, S. (2000). Eur. J. Cancer 36, 1631-1639.PubMedGoogle Scholar
  18. Hildebrandt, M., Lacombe, M., Mesnildrey, S., and Veron, M. (1995). Nucleic. Acids Res. 23, 3858-3864.PubMedGoogle Scholar
  19. Howlett, A. R., Petersen, O. W., Steeg, P. S., and Bissell, M. J. (1994). J. Natl. Cancer Inst. 86, 1838-1844.PubMedGoogle Scholar
  20. Iizuka, N., Miyamoto, K., Tangoku, A., Hayashi, H., Yoshino, S., Yoshimura, K., Hirose, K., Yoshida, H., and Oka, M. (2000). Br. J. Cancer 83, 1209-1215.PubMedGoogle Scholar
  21. Iizuka, N., Tangoku, A., Hayashi, H., Yosino, S., Abe, T., Morioka, T., and Oka, M. (1999).Cancer Lett. 138, 139-144.PubMedGoogle Scholar
  22. Inoue, H., Takahashi, M., Oomori, A., Sekiguchi, M., and Yoshioka, T. (1996). Biochem. Biophys. Res. Comm. 218, 887-892.PubMedGoogle Scholar
  23. Jacobs, D., Glossip, D., Xing, H., Muslin, A., and Kornfeld, K. (1999). Genes Dev. 13, 163-175.PubMedGoogle Scholar
  24. Jiang, W., Hiscox, S., Bryce, R., Horrobin, D., and Mansel, R. (1988). Br. J. Cancer 77, 731-738.Google Scholar
  25. Kim, J., Lee, S., Kim, J., Lee, T., Hirata, M., Suh, P., and Ryu, S. (2002). Biochemistry 41, 3414-3421.PubMedGoogle Scholar
  26. Kornfield, K., Hom, D., and Horvitz, H. (1995). Cell 83, 903-913.PubMedGoogle Scholar
  27. Lacombe, M.-L., Milon, L., Munier, A., Mehus, J., and Lambeth, D. (2000). J. Bioenerg. Biomembr. 32, 247-258.PubMedGoogle Scholar
  28. Lascu, I., Giartosio, A., Ransac, S., and Erent, M. (2000). J. Bioenerg. Biomembr. 32, 227-236.PubMedGoogle Scholar
  29. Leone, A., Flatow, U., King, C. R., Sandeen, M. A., Margulies, I. M. K., Liotta, L. A., and Steeg, P. S. (1991). Cell 65, 25-35.PubMedGoogle Scholar
  30. Leone, A., Flatow, U., Van Houtte, K., and Steeg, P. S. (1993). Oncogene 8, 2325-2333.PubMedGoogle Scholar
  31. Leone, A., Seeger, R. C., Hong, C. M., Hu, Y. Y., Arboleda, M. J., Brodeur, G. M., Stram, D., Slamon, D. J., and Steeg, P. S. (1993). Oncogene 8, 855-865.PubMedGoogle Scholar
  32. Lin, K., Shieh, H., and Hsu, H. (2000). Endocrinology 141, 2540-2547.PubMedGoogle Scholar
  33. Liu, F., Qi, H.-L., and Chen, H.-L. (2000). J. Cancer Res. Clin. Oncol. 126, 85-90.PubMedGoogle Scholar
  34. Lu, Q., Park, H., Egger, L., and Inouye, M. (1996). J. Biol. Chem. 271, 32886-32893.PubMedGoogle Scholar
  35. Ma, D., Xing, Z., Liu, B., Pedigo, N., Zimmer, S., Bai, Z., Postel, E., and Kaetzel, D. (2002). J. Biol. Chem. 277, 1560-1567.PubMedGoogle Scholar
  36. MacDonald, N., Freije, J., Stracke, M., Manrow, R., and Steeg, P. (1996). J. Biol. Chem. 271, 25107-25116.PubMedGoogle Scholar
  37. Michelotti, E., Sanford, S., Freije, J., MacDonald, N., Steeg, P., and Levens, D. (1997). J. Biol. Chem. 272, 22526-22530.PubMedGoogle Scholar
  38. Miele, M. E., Rosa, A. D. L., Lee, J. H., Hicks, D. J., Dennis, J. U., Steeg, P. S., and Welch, D. R. (1997). Clin. Exp. Metastasis 15, 259-265.PubMedGoogle Scholar
  39. Miyazaki, H., Fukuda, M., Ishijima, Y., Negishi, A., Hirayama, R., Ishikawa, N., Amagasa, T., and Kimura, N. (1999). Clin. Cancer Res. 5, 4301-4307.PubMedGoogle Scholar
  40. Muller, J., Ory, S., Copeland, T., Piwnica-Worms, H., and Morrison, D. (2001). Mol. Cell 8, 983-993.PubMedGoogle Scholar
  41. Naumov, G., MacDonald, I., Weinmeister, P., Kerkvliet, N., Nadkarni, K., Wilson, S., Morris, V., Groom, A., and Chambers, A. (2002). Cancer Res. 62, 2162-2168.PubMedGoogle Scholar
  42. Otero, A., Doyle, M., Hartsough, M., and Steeg, P. (1999). Biochim. Biophys. Acta 1449, 157-168.PubMedGoogle Scholar
  43. Otsuki, Y., Tanaka, M., Yoshii, S., Kawazoe, N., Nakaya, K., and Sugimura, H. (2001). Proc. Natl. Acad. Sci. U.S.A. 98, 4385-4390.PubMedGoogle Scholar
  44. Ouatas, T., Clare, S., Hartsough, M., DeLaRosa, A., and Steeg, P. (2002). Clin. Exp. Metastasis 19, 35-42.PubMedGoogle Scholar
  45. Parhar, R. S., Shi, Y., Zou, M., Farid, N. R., Ernst, P., and Al-Sedairy, S. (1995). Int. J. Cancer 60, 204-210.PubMedGoogle Scholar
  46. Postel, E. (1999). J. Biol. Chem. 274, 22821-22829.PubMedGoogle Scholar
  47. Postel, E., Abramczyk, B., Gursky, S., and Xu, Y. (2002). Biochemistry 41, 6330-6337.PubMedGoogle Scholar
  48. Postel, E. H., Berberich, S. J., Flint, S. J., and Ferrone, C. A. (1993). Science 261, 478-480.PubMedGoogle Scholar
  49. Rosengard, A. M., Krutzsch, H. C., Shearn, A., Biggs, J. R., Barker, E., Margulies, I. M. K., King, C. R., Liotta, L. A., and Steeg, P. S. (1989). Nature 342, 177-180.PubMedGoogle Scholar
  50. Russell, R., Pedersen, A., Kantor, J., Geisinger, K., Long, R., Zbieranski, N., Townsend, A., Shelton, B., Brunner, N., and Kute, T. (1998). Br. J. Cancer 78, 710-717.PubMedGoogle Scholar
  51. Scambia, G., Ferrandina, G., Marone, M., Panici, P. B., Giannitelli, C., Piantelli, M., Leone, A., and Manusco, S. (1996). J. Clin. Oncol. 14, 334-342.PubMedGoogle Scholar
  52. Slamon, D., Leyland-Jones, B., Shak, S., Fuchs, H., Payton, V., Bajamonde, A., Fleming, T., Eiermann, W., Wolter, J., Pagram, M., Baselga, J., and Norton, L. (2001). New Engl. J. Med. 344, 783-792.PubMedGoogle Scholar
  53. Steeg, P. (2000). Br. Cancer Res. 2, 396-399.Google Scholar
  54. Steeg, P. S., Bevilacqua, G., Kopper, L., Thorgeirsson, U. P., Talmadge, J. E., Liotta, L. A., and Sobel, M. E. (1988). J. Natl. Cancer Inst. 80, 200-204.PubMedGoogle Scholar
  55. Stewart, S., Sundaram, M., Zhang, Y., Lee, J., Han, M., and Guan, K. (1999). Mol. Cell. Biol. 19, 5523-5534.PubMedGoogle Scholar
  56. Sundaram, M., and Han, M. (1995). Cell 83, 889-901.PubMedGoogle Scholar
  57. Tagashira, H., Hamazaki, K., Tanaka, N., Gao, C., and Namba, M. (1998). Int. J. Mol. Med. 2, 65-68.PubMedGoogle Scholar
  58. Therrien, M., Chang, H., Solomon, N., Karim, F., Wassarman, D., and Rubin, G. (1995). Cell 83, 879-888.PubMedGoogle Scholar
  59. Wagner, P. D., Steeg, P. S., and Vu, N.-D. (1997). Proc. Natl. Acad. Sci. U.S.A. 94, 9000-9005.PubMedGoogle Scholar
  60. Wagner, P., and Vu, N.-D. (1995). J. Biol. Chem. 270, 21758-21764.PubMedGoogle Scholar
  61. Wagner, P., and Vu, N. (2000a). J. Biol. Chem. 275, 35570-35576.PubMedGoogle Scholar
  62. Wagner, P., and Vu, N.-D. (2000b). Biochem. J. 346, 623-630.PubMedGoogle Scholar
  63. Wallet, V., Mutzel, R., Troll, H., Barzu, O., Wurster, B., Veron, M., and Lacombe, M. L. (1990). J. Natl. Cancer Inst. 82, 1199-1202.PubMedGoogle Scholar
  64. Wang, X., Wu, G., Zhang, M., Guo, M., Zhang, H., and Sun, X. (2000). Oncol. Rep. 7, 241-244.PubMedGoogle Scholar
  65. Welch, D., Steeg, P., and Rinker-Schaeffer, S. (2000). Br. Cancer Res. 2, 408-416.Google Scholar
  66. Xing, H., Kornfeld, K., and Muslin, A. (1997). Curr. Biol. 7, 294-300.PubMedGoogle Scholar
  67. Xu, J., Liu, L., Deng, F., Timmons, L., Hersperger, E., Steeg, P., Veron, M., and Shearn, A. (1996). Dev. Biol. 177, 544-557.Google Scholar
  68. Yoshida, B., Sokoloff, M., Welch, D., and Rinker-Schaeffer, C. (2000). J. Natl. Cancer Inst. 92, 1717-1730.PubMedGoogle Scholar
  69. Yu, W., Fantl, W., Harrowe, G., and Williams, L. (1997). Curr. Biol. 8, 56-64.Google Scholar

Copyright information

© Plenum Publishing Corporation 2003

Authors and Affiliations

  • Taoufik Ouatas
    • 1
    Email author
  • Massimiliano Salerno
    • 1
  • Diane Palmieri
    • 1
  • Patricia S. Steeg
    • 1
  1. 1.Women's Cancers Section, Laboratory of Pathology, Center for Cancer ResearchNational Cancer InstituteBethesda

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