Abstract
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.
Similar content being viewed by others
References
Baba, H., Urano, T., Okada, K., Furukawa, K., Nakayama, E., Tanaka, H., Iwasaki, K., and Shiku, H. (1995). Cancer Res. 55, 1977-1981.
Bell, B., Xing, H., Yan, K., Gautam, N., and Muslin, A. (1999). J. Biol. Chem. 274, 7982-7986.
Bhujwalla, Z., Aboagye, E., Gilles, R., Chack, V., Mendola, C., and Backer, J. (1999). Magn. Reson. Med. 41, 897-903.
Cacace, A., Michaud, N., Therrien, M., Mathes, K., Copeland, T., Rubin, G., and Morrison, D. (1999). Mol. Cell. Biol. 19, 229-240.
Chambers, A., Groom, A., and MacDonald, I. (2002). Nat. Cancer Rev. 2, 563-572.
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.
Cho, S., Lee, N., Jung, Y., Lee, H., Lee, K., Kim, E., and Chae, S. (2001). Biochem. Biophys. Res. Comm. 289, 738-743.
Denouel-Galy, A., Douville, E., Warne, P., Papin, C., Laugier, D., Calothy, G., Downward, J., and Eychene, A. (1997). Curr. Biol. 8, 46-55.
Engel, M., Veron, M., Theisinger, B., Lacombe, M.-L., Seib, T., Dooley, S., and Welter, C. (1995). Eur. J. Biochem. 234, 200-207.
Ferguson, A., Flatow, U., MacDonald, N., Larminant, F., Bohr, V., and Steeg, P. (1996). Cancer Res. 56, 2931-2935.
Freije, J. M. P., Blay, P., MacDonald, N. J., Manrow, R. E., and Steeg, P. S. (1997). J. Biol. Chem. 272, 5525-5532.
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.
Hartsough, M., Clare, S., Mair, M., Elkahloun, A., Sgroi, D., Osborne, C., Clark, G., and Steeg, P. (2001). Cancer Res. 61, 2320-2327.
Hartsough, M., Morrison, D., Salerno, M., Palmieri, D., Ouatas, T., Mair, M., Patrick, J., and Steeg, P. (2002). J. Biol. Chem. 277, 32389-32399.
Hartsough, M., and Steeg, P. (2000). J. Bioenerg. Biomembr. 32, 301-308.
Heimann, R., Ferguson, D., and Hellman, S. (1998). Cancer Res. 58, 2766-2771.
Heimann, R., and Hellman, S. (2000). Eur. J. Cancer 36, 1631-1639.
Hildebrandt, M., Lacombe, M., Mesnildrey, S., and Veron, M. (1995). Nucleic. Acids Res. 23, 3858-3864.
Howlett, A. R., Petersen, O. W., Steeg, P. S., and Bissell, M. J. (1994). J. Natl. Cancer Inst. 86, 1838-1844.
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.
Iizuka, N., Tangoku, A., Hayashi, H., Yosino, S., Abe, T., Morioka, T., and Oka, M. (1999).Cancer Lett. 138, 139-144.
Inoue, H., Takahashi, M., Oomori, A., Sekiguchi, M., and Yoshioka, T. (1996). Biochem. Biophys. Res. Comm. 218, 887-892.
Jacobs, D., Glossip, D., Xing, H., Muslin, A., and Kornfeld, K. (1999). Genes Dev. 13, 163-175.
Jiang, W., Hiscox, S., Bryce, R., Horrobin, D., and Mansel, R. (1988). Br. J. Cancer 77, 731-738.
Kim, J., Lee, S., Kim, J., Lee, T., Hirata, M., Suh, P., and Ryu, S. (2002). Biochemistry 41, 3414-3421.
Kornfield, K., Hom, D., and Horvitz, H. (1995). Cell 83, 903-913.
Lacombe, M.-L., Milon, L., Munier, A., Mehus, J., and Lambeth, D. (2000). J. Bioenerg. Biomembr. 32, 247-258.
Lascu, I., Giartosio, A., Ransac, S., and Erent, M. (2000). J. Bioenerg. Biomembr. 32, 227-236.
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.
Leone, A., Flatow, U., Van Houtte, K., and Steeg, P. S. (1993). Oncogene 8, 2325-2333.
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.
Lin, K., Shieh, H., and Hsu, H. (2000). Endocrinology 141, 2540-2547.
Liu, F., Qi, H.-L., and Chen, H.-L. (2000). J. Cancer Res. Clin. Oncol. 126, 85-90.
Lu, Q., Park, H., Egger, L., and Inouye, M. (1996). J. Biol. Chem. 271, 32886-32893.
Ma, D., Xing, Z., Liu, B., Pedigo, N., Zimmer, S., Bai, Z., Postel, E., and Kaetzel, D. (2002). J. Biol. Chem. 277, 1560-1567.
MacDonald, N., Freije, J., Stracke, M., Manrow, R., and Steeg, P. (1996). J. Biol. Chem. 271, 25107-25116.
Michelotti, E., Sanford, S., Freije, J., MacDonald, N., Steeg, P., and Levens, D. (1997). J. Biol. Chem. 272, 22526-22530.
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.
Miyazaki, H., Fukuda, M., Ishijima, Y., Negishi, A., Hirayama, R., Ishikawa, N., Amagasa, T., and Kimura, N. (1999). Clin. Cancer Res. 5, 4301-4307.
Muller, J., Ory, S., Copeland, T., Piwnica-Worms, H., and Morrison, D. (2001). Mol. Cell 8, 983-993.
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.
Otero, A., Doyle, M., Hartsough, M., and Steeg, P. (1999). Biochim. Biophys. Acta 1449, 157-168.
Otsuki, Y., Tanaka, M., Yoshii, S., Kawazoe, N., Nakaya, K., and Sugimura, H. (2001). Proc. Natl. Acad. Sci. U.S.A. 98, 4385-4390.
Ouatas, T., Clare, S., Hartsough, M., DeLaRosa, A., and Steeg, P. (2002). Clin. Exp. Metastasis 19, 35-42.
Parhar, R. S., Shi, Y., Zou, M., Farid, N. R., Ernst, P., and Al-Sedairy, S. (1995). Int. J. Cancer 60, 204-210.
Postel, E. (1999). J. Biol. Chem. 274, 22821-22829.
Postel, E., Abramczyk, B., Gursky, S., and Xu, Y. (2002). Biochemistry 41, 6330-6337.
Postel, E. H., Berberich, S. J., Flint, S. J., and Ferrone, C. A. (1993). Science 261, 478-480.
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.
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.
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.
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.
Steeg, P. (2000). Br. Cancer Res. 2, 396-399.
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.
Stewart, S., Sundaram, M., Zhang, Y., Lee, J., Han, M., and Guan, K. (1999). Mol. Cell. Biol. 19, 5523-5534.
Sundaram, M., and Han, M. (1995). Cell 83, 889-901.
Tagashira, H., Hamazaki, K., Tanaka, N., Gao, C., and Namba, M. (1998). Int. J. Mol. Med. 2, 65-68.
Therrien, M., Chang, H., Solomon, N., Karim, F., Wassarman, D., and Rubin, G. (1995). Cell 83, 879-888.
Wagner, P. D., Steeg, P. S., and Vu, N.-D. (1997). Proc. Natl. Acad. Sci. U.S.A. 94, 9000-9005.
Wagner, P., and Vu, N.-D. (1995). J. Biol. Chem. 270, 21758-21764.
Wagner, P., and Vu, N. (2000a). J. Biol. Chem. 275, 35570-35576.
Wagner, P., and Vu, N.-D. (2000b). Biochem. J. 346, 623-630.
Wallet, V., Mutzel, R., Troll, H., Barzu, O., Wurster, B., Veron, M., and Lacombe, M. L. (1990). J. Natl. Cancer Inst. 82, 1199-1202.
Wang, X., Wu, G., Zhang, M., Guo, M., Zhang, H., and Sun, X. (2000). Oncol. Rep. 7, 241-244.
Welch, D., Steeg, P., and Rinker-Schaeffer, S. (2000). Br. Cancer Res. 2, 408-416.
Xing, H., Kornfeld, K., and Muslin, A. (1997). Curr. Biol. 7, 294-300.
Xu, J., Liu, L., Deng, F., Timmons, L., Hersperger, E., Steeg, P., Veron, M., and Shearn, A. (1996). Dev. Biol. 177, 544-557.
Yoshida, B., Sokoloff, M., Welch, D., and Rinker-Schaeffer, C. (2000). J. Natl. Cancer Inst. 92, 1717-1730.
Yu, W., Fantl, W., Harrowe, G., and Williams, L. (1997). Curr. Biol. 8, 56-64.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ouatas, T., Salerno, M., Palmieri, D. et al. Basic and Translational Advances in Cancer Metastasis: Nm23. J Bioenerg Biomembr 35, 73–79 (2003). https://doi.org/10.1023/A:1023497924277
Issue Date:
DOI: https://doi.org/10.1023/A:1023497924277