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NSAID Activated Gene (NAG-1), a Modulator of Tumorigenesis

  • Accepted : 2006.08.24
  • Published : 2006.11.30

Abstract

The NSAID activated gene (NAG-1), a member of the TGF-$\beta$ superfamily, is involved in tumor progression and development. The over-expression of NAG-1 in cancer cells results in growth arrest and increase in apoptosis, suggesting that NAG-1 has anti-tumorigenic activity. This conclusion is further supported by results of experiments with transgenic mice that ubiquitously express human NAG-1. These transgenic mice are resistant to the development of intestinal tumors following treatment with azoxymethane or by introduction of a mutant APC gene. In contrast, other data suggest a pro-tumorigenic role for NAG-1, for example, high expression of NAG-1 is frequently observed in tumors. NAG-1 may be like other members of the TGF-$\beta$ superfamily, acting as a tumor suppressor in the early stages, but acting pro-tumorigenic at the later stages of tumor progression. The expression of NAG-1 can be increased by treatment with drugs and chemicals documented to prevent tumor formation and development. Most notable is the increase in NAG-1 expression by the inhibitors of cyclooxygenases that prevent human colorectal cancer development. The regulation of NAG-1 is complex, but these agents act through either p53 or EGR-1 related pathways. In addition, an increase in NAG-1 is observed in inhibition of the AKT/GSK-$3{\beta}$ pathway, suggesting NAG-1 alters cell survival. Thus, NAG-1 expression is regulated by tumor suppressor pathways and appears to modulate tumor progression.

Keywords

Anti-tumorigenic;Cancer;Cox inhibitor;Min mice;NAG-1;Tumor suppressor

References

  1. Albertoni, M., Shaw, P. H., Nozaki, M., Godard, S., Tenan, M., Hamou, M. F., Fairlie, D. W., Breit, S. N., Paralkar, V. M., de Tribolet, N., Van Meir, E. G. and Hegi, M. E. (2002) Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1. Oncogene 21, 4212-4219 https://doi.org/10.1038/sj.onc.1205610
  2. Baek, S. J. and Eling, T. E. (2006a) Changes in gene expression contribute to cancer prevention by COX inhibitors. Prog. Lipid Res. 45, 1-16 https://doi.org/10.1016/j.plipres.2005.10.001
  3. Baek, S. J., Horowitz, J. M. and Eling, T. E. (2001a) Molecular cloning and characterization of human nonsteroidal antiinflammatory drug-activated gene promoter. Basal transcription is mediated by Sp1 and Sp3. J. Biol. Chem. 276, 33384-33392 https://doi.org/10.1074/jbc.M101814200
  4. Baek, S. J., Kim, J. S., Moore, S. M., Lee, S. H., Martinez, J. and Eling, T. E. (2005) Cyclooxygenase inhibitors induce the expression of the tumor suppressor gene EGR-1, which results in the up-regulation of NAG-1, an antitumorigenic protein. Mol. Pharmacol. 67, 356-364 https://doi.org/10.1124/mol.104.005108
  5. Baek, S. J., Kim, J. S., Nixon, J. B., DiAugustine, R. P. and Eling, T. E. (2004) Expression of NAG-1, a transforming growth factor-beta superfamily member, by troglitazone requires the early growth response gene EGR-1. J. Biol. Chem. 279, 6883-6892 https://doi.org/10.1074/jbc.M305295200
  6. Baek, S. J., Kim, K. S., Nixon, J. B., Wilson, L. C. and Eling, T. E. (2001b). Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities. Mol. Pharmacol. 59, 901-908 https://doi.org/10.1124/mol.59.4.901
  7. Baek, S. J., Okazaki, R., Lee, S. H., Martinez, J., Kim, J. S., Yamaguchi, K., Mishina, Y., Martin, D. W., Shoieb, A., McEntee, M. F. and Eling, T. E. (2006b) Nonsteroidal antiinflammatory drug activated gene-1 overexpression in transgenic mice suppresses intestinal neoplasia. Gastroenterology in press
  8. Baek, S. J., Wilson, L. C. and Eling, T. E. (2002a) Resveratrol enhances the expression of non-steroidal anti-inflammatory drug-activated gene (NAG-1) by increasing the expression of p53. Carcinogenesis 23, 425-432 https://doi.org/10.1093/carcin/23.3.425
  9. Baek, S. J., Wilson, L. C., Lee, C. H. and Eling, T. E. (2002b) Dual function of nonsteroidal anti-inflammatory drugs (NSAIDs): inhibition of cyclooxygenase and induction of NSAID-activated gene. J. Pharmacol. Exp. Ther. 301, 1126- 1131 https://doi.org/10.1124/jpet.301.3.1126
  10. Bauskin, A. R., Brown, D. A., Junankar, S., Rasiah, K. K., Eggleton, S., Hunter, M., Liu, T., Smith, D., Kuffner, T., Pankhurst, G. J. et al. (2005) The propeptide mediates formation of stromal stores of PROMIC-1: role in determining prostate cancer outcome. Cancer Res. 65, 2330-2336 https://doi.org/10.1158/0008-5472.CAN-04-3827
  11. Bauskin, A. R., Zhang, H. P., Fairlie, W. D., He, X. Y., Russell, P. K., Moore, A. G., Brown, D. A., Stanley, K. K. and Breit, S. N. (2000) The propeptide of macrophage inhibitory cytokine (MIC-1), a TGF-beta superfamily member, acts as a quality control determinant for correctly folded MIC-1. Embo J. 19, 2212-2220 https://doi.org/10.1093/emboj/19.10.2212
  12. Bootcov, M. R., Bauskin, A. R., Valenzuela, S. M., Moore, A. G., Bansal, M., He, X. Y., Zhang, H. P., Donnellan, M., Mahler, S., Pryor, K., Walsh, B. J., Nicholson, R. C., Fairlie, W. D., Por, S. B, Robbins, J. M. and Breit, S. N. (1997) MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc. Natl. Acad. Sci. USA 94, 11514-11519 https://doi.org/10.1073/pnas.94.21.11514
  13. Bottner, M., Suter-Crazzolara, C., Schober, A. and Unsicker, K. (1999) Expression of a novel member of the TGF-beta superfamily, growth/differentiation factor-15/macrophageinhibiting cytokine-1 (GDF-15/MIC-1) in adult rat tissues. Cell Tissue Res 297, 103-110 https://doi.org/10.1007/s004410051337
  14. Bottone, F. G., Jr., Baek, S. J., Nixon, J. B. and Eling, T. E. (2002) Diallyl disulfide (DADS) induces the antitumorigenic NSAID-activated gene (NAG-1) by a p53-dependent mechanism in human colorectal HCT 116 cells. J. Nutr. 132, 773-778 https://doi.org/10.1093/jn/132.4.773
  15. Brown, D. A., Ward, R. L., Buckhaults, P., Liu, T., Romans, K. E., Hawkins, N. J., Bauskin, A. R., Kinzler, K. W., Vogelstein, B. and Breit, S. N. (2003) MIC-1 serum level and genotype: associations with progress and prognosis of colorectal carcinoma. Clin. Cancer Res. 9, 2642-2650
  16. Detmer, K., Steele, T. A., Shoop, M. A. and Dannawi, H. (1999). Lineage-restricted expression of bone morphogenetic protein genes in human hematopoietic cell lines. Blood Cells Mol. Dis. 25, 310-323 https://doi.org/10.1006/bcmd.1999.0259
  17. Fairlie, W. D., Russell, P. K., Wu, W. M., Moore, A. G., Zhang, H. P., Brown, P. K., Bauskin, A. R. and Breit, S. N. (2001) Epitope mapping of the transforming growth factor-beta superfamily protein, macrophage inhibitory cytokine-1 (MIC-1): identification of at least five distinct epitope specificities. Biochemistry 40, 65-73 https://doi.org/10.1021/bi001064p
  18. Fearon, E. R. and Vogelstein, B. (1990) A genetic model for colorectal tumorigenesis. Cell 61, 759-767 https://doi.org/10.1016/0092-8674(90)90186-I
  19. Hayes, V. M., Severi, G., Southey, M. C., Padilla, E. J., English, D. R., Hopper, J. L., Giles, G. G. and Sutherland, R. L. (2006) Macrophage inhibitory cytokine-1 H6D polymorphism, prostate cancer risk, and survival. Cancer Epidemiol. Biomarkers Prev. 15, 1223-1225 https://doi.org/10.1158/1055-9965.EPI-06-0063
  20. Hsiao, E. C., Koniaris, L. G., Zimmers-Koniaris, T., Sebald, S. M., Huynh, T. V. and Lee, S. J. (2000) Characterization of growthdifferentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury. Mol. Cell. Biol. 20, 3742-3751 https://doi.org/10.1128/MCB.20.10.3742-3751.2000
  21. Karan, D., Chen, S. J., Johansson, S. L., Singh, A. P., Paralkar, V. M., Lin, M. F. and Batra, S. K. (2003) Dysregulated expression of MIC-1/PDF in human prostate tumor cells. Biochem. Biophys. Res. Commun. 305, 598-604 https://doi.org/10.1016/S0006-291X(03)00823-4
  22. Kim, K. S., Baek, S. J., Flake, G. P., Loftin, C. D., Calvo, B. F. and Eling, T. E. (2002). Expression and regulation of nonsteroidal anti-inflammatory drug-activated gene (NAG-1) in human and mouse tissue. Gastroenterology 122, 1388-1398 https://doi.org/10.1053/gast.2002.32972
  23. Kim, K. S., Shin, J. H., Baek, S. J. and Yoon, J. H. (2003) Expression of non-steroidal anti-inflammatory drug-activated gene-1 in human nasal mucosa and cultured nasal epithelial cells: a preliminary investigation. Acta Otolaryngol. 123, 857- 861 https://doi.org/10.1080/00016480310000584b
  24. Kim, K. S., Yoon, J. H., Kim, J. K., Baek, S. J., Eling, T. E., Lee, W. J., Ryu, J. H., Lee, J. G., Lee, J. H. and Yoo, J. B. (2004) Cyclooxygenase inhibitors induce apoptosis in oral cavity cancer cells by increased expression of nonsteroidal antiinflammatory drug-activated gene. Biochem. Biophys. Res. Commun. 325, 1298-1303 https://doi.org/10.1016/j.bbrc.2004.10.176
  25. Kinzler, K. W., Nilbert, M. C., Vogelstein, B., Bryan, T. M., Levy, D. B., Smith, K. J., Preisinger, A. C., Hamilton, S. R., Hedge, P., Markham, A. and et al. (1991) Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science 251, 1366-1370 https://doi.org/10.1126/science.1848370
  26. Kinzler, K. W. and Vogelstein, B. (1996) Lessons from hereditary colorectal cancer. Cell 87, 159-170 https://doi.org/10.1016/S0092-8674(00)81333-1
  27. Lambert, J. R., Kelly, J. A., Shim, M., Huffer, W. E., Nordeen, S. K., Baek, S. J., Eling, T. E. and Lucia, M. S. (2006) Prostate derived factor in human prostate cancer cells: Gene induction by vitamin D via a p53-dependent mechanism and inhibition of prostate cancer cell growth. J. Cell. Physiol. 208, 566-574 https://doi.org/10.1002/jcp.20692
  28. Lawton, L. N., Bonaldo, M. F., Jelenc, P. C., Qiu, L., Baumes, S. A., Marcelino, R. A., Jesus, G. M., Wellington, S., Knowles, J. A., Warburton, D., Brown, S. and Soares, M. B. (1997) Identification of a novel member of the TGF-beta superfamily highly expressed in human placenta. Gene 203, 17-26 https://doi.org/10.1016/S0378-1119(97)00485-X
  29. Lee, D. H., Yang, Y., Lee, S. J., Kim, K. Y., Koo, T. H., Shin, S. M., Song, K. S., Lee, Y. H., Kim, Y. J., Lee, J. J., Choi, I., Lee, J. H. (2003) Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system. Cancer Res. 63, 4648-4655
  30. Lee, S. H., Kim, J. S., Yamaguchi, K., Eling, T. E. and Baek, S. J. (2005) Indole-3-carbinol and 3,3'-diindolylmethane induce expression of NAG-1 in a p53-independent manner. Biochem. Biophys. Res. Commun. 328, 63-69 https://doi.org/10.1016/j.bbrc.2004.12.138
  31. Lee, S. H., Yamaguchi, K., Kim, J. S., Eling, T. E., Safe, S., Park, Y. and Baek, S. J. (2006) Conjugated linoleic acid stimulates an anti-tumorigenic protein NAG-1 in an isomer specific manner. Carcinogenesis 27, 972-981 https://doi.org/10.1093/carcin/bgi268
  32. Li, P. X., Wong, J., Ayed, A., Ngo, D., Brade, A. M., Arrowsmith, C., Austin, R. C. and Klamut, H. J. (2000) Placental transforming growth factor-beta is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression. J. Biol. Chem. 275, 20127-20135
  33. Lindmark, F., Zheng, S. L., Wiklund, F., Bensen, J., Balter, K. A., Chang, B., Hedelin, M., Clark, J., Stattin, P., Meyers, D. A., Adami, H. O, Isaacs, W., Grönberg, H. and Xu, J. (2004) H6D polymorphism in macrophage-inhibitory cytokine-1 gene associated with prostate cancer. J. Natl. Cancer Inst. 96, 1248- 1254 https://doi.org/10.1093/jnci/djh227
  34. Liu, T., Bauskin, A. R., Zaunders, J., Brown, D. A., Pankhurst, S., Russell, P. J. and Breit, S. N. (2003) Macrophage inhibitory cytokine 1 reduces cell adhesion and induces apoptosis in prostate cancer cells. Cancer Res. 63, 5034-5040
  35. Martinez, J. M., Sali, T., Okazaki, R., Anna, C., Hollingshead, M., Hose, C., Monks, A., Walker, N. J., Baek, S. J. and Eling, T. E. (2006) Drug-induced expression of nonsteroidal antiinflammatory drug-activated gene/macrophage inhibitory cytokine-1/prostate-derived factor, a putative tumor suppressor, inhibits tumor growth. J. Pharmacol. Exp. Ther. 318, 899-906 https://doi.org/10.1124/jpet.105.100081
  36. Newman, D., Sakaue, M., Koo, J. S., Kim, K. S., Baek, S. J., Eling, T. and Jetten, A. M. (2003) Differential regulation of nonsteroidal anti-inflammatory drug-activated gene in normal human tracheobronchial epithelial and lung carcinoma cells by retinoids. Mol. Pharmacol. 63, 557-564 https://doi.org/10.1124/mol.63.3.557
  37. Paralkar, V. M., Vail, A. L., Grasser, W. A., Brown, T. A., Xu, H., Vukicevic, S., Ke, H. Z., Qi, H., Owen, T. A. and Thompson, D. D. (1998) Cloning and characterization of a novel member of the transforming growth factor-beta/bone morphogenetic protein family. J. Biol. Chem. 273, 13760-13767 https://doi.org/10.1074/jbc.273.22.13760
  38. Shim, M. and Eling, T. E. (2005). Protein kinase C-dependent regulation of NAG-1/placental bone morphogenic protein/MIC- 1 expression in LNCaP prostate carcinoma cells. J. Biol. Chem. 280, 18636-18642 https://doi.org/10.1074/jbc.M414613200
  39. Tan, M., Wang, Y., Guan, K. and Sun, Y. (2000) PTGF-beta, a type beta transforming growth factor (TGF-beta) superfamily member, is a p53 target gene that inhibits tumor cell growth via TGF-beta signaling pathway. Proc. Natl. Acad. Sci. USA 97, 109-114 https://doi.org/10.1073/pnas.97.1.109
  40. Thomas, R., True, L. D., Lange, P. H. and Vessella, R. L. (2001) Placental bone morphogenetic protein (PLAB) gene expression in normal, pre-malignant and malignant human prostate: relation to tumor development and progression. Int. J. Cancer 93, 47-52
  41. Vogelstein, B., Fearon, E. R., Hamilton, S. R., Kern, S. E., Preisinger, A. C., Leppert, M., Nakamura, Y., White, R., Smits, A. M. and Bos, J. L. (1988) Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 319, 525-532 https://doi.org/10.1056/NEJM198809013190901
  42. Welsh, J. B., Sapinoso, L. M., Su, A. I., Kern, S. G., Wang- Rodriguez, J., Moskaluk, C. A., Frierson, H. F., Jr. and Hampton, G. M. (2001) Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. Cancer Res. 61, 5974-5978
  43. Wilson, L. C., Baek, S. J., Call, A. and Eling, T. E. (2003) Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) is induced by genistein through the expression of p53 in colorectal cancer cells. Int. J. Cancer 105, 747-753 https://doi.org/10.1002/ijc.11173
  44. Yamaguchi, K., Lee, S. H., Eling, T. E. and Baek, S. J. (2004). Identification of nonsteroidal anti-inflammatory drug-activated gene (NAG-1) as a novel downstream target of phosphatidylinositol 3-kinase/AKT/GSK-3beta pathway. J. Biol. Chem. 279, 49617-49623 https://doi.org/10.1074/jbc.M408796200
  45. Yamaguchi, K., Lee, S. H., Eling, T. E. and Baek, S. J. (2006). A novel peroxisome proliferator-activated receptor gamma ligand, MCC-555, induces apoptosis via posttranscriptional regulation of NAG-1 in colorectal cancer cells. Mol. Cancer Ther. 5, 1352-1361 https://doi.org/10.1158/1535-7163.MCT-05-0528

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