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

  • Accepted : 2006.08.24
  • Published : 2006.11.30


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.


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


  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  18. Fearon, E. R. and Vogelstein, B. (1990) A genetic model for colorectal tumorigenesis. Cell 61, 759-767
  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
  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
  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
  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
  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
  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
  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
  26. Kinzler, K. W. and Vogelstein, B. (1996) Lessons from hereditary colorectal cancer. Cell 87, 159-170
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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

Cited by

  1. Mechanisms of Action of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Mesalazine in the Chemoprevention of Colorectal Cancer vol.14, pp.9, 2013,
  2. Proteasome inhibitor MG132 induces NAG-1/GDF15 expression through the p38 MAPK pathway in glioblastoma cells vol.430, pp.4, 2013,
  3. Serum hepcidin and growth differentiation factor-15 (GDF-15) levels in polycythemia vera and essential thrombocythemia vol.91, pp.3, 2013,
  4. Expression of macrophage inhibitory cytokine-1 in prostate cancer bone metastases induces osteoclast activation and weight loss vol.69, pp.6, 2009,
  5. Novel therapeutics with enhanced biological activity generated by the strategic introduction of silicon isosteres into known drug scaffolds vol.68, pp.4, 2007,
  6. Prognostic Value of Gene Methylation and Clinical Factors in Non–Muscle-Invasive Upper Tract Urothelial Carcinoma After Radical Nephroureterectomy vol.14, pp.4, 2016,
  7. Expression of Macrophage Inhibitory Cytokine-1 in Benign and Malignant Prostatic Tissues: Implications for Prostate Carcinogenesis and Progression of Prostate Cancer vol.6, pp.3, 2010,
  8. Silibinin induces apoptosis of HT29 colon carcinoma cells through early growth response-1 (EGR-1)-mediated non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) up-regulation vol.211, 2014,
  9. Elevated growth differentiation factor 15 expression predicts poor prognosis in epithelial ovarian cancer patients vol.37, pp.7, 2016,
  10. Serum Growth Differentiation Factor 15 Levels in Newly Diagnosed Multiple Myeloma Patients vol.131, pp.3, 2014,
  11. Potential Therapeutic Role of Hispidulin in Gastric Cancer through Induction of Apoptosis via NAG-1 Signaling vol.2013, 2013,
  12. Obesity, Rather Than Diet, Drives Epigenomic Alterations in Colonic Epithelium Resembling Cancer Progression vol.19, pp.4, 2014,
  13. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin vol.13, pp.9, 2007,
  14. Role of nonsteroidal anti-inflammatory drug-activated gene-1 in docetaxel-induced cell death of human colorectal cancer cells with different p53 status vol.34, pp.2, 2011,
  15. From steroid receptors to cytokines: The thermodynamics of self-associating systems vol.159, pp.1, 2011,
  16. Serum iron metabolism and erythropoiesis in patients with myelodysplastic syndrome not receiving RBC transfusions vol.38, pp.5, 2014,
  17. Taiwanin A targets non-steroidal anti-inflammatory drug-activated gene-1 in human lung carcinoma vol.99, 2014,
  18. Molecular Mechanisms of Hepcidin Regulation: Implications for the Anemia of CKD vol.55, pp.4, 2010,
  19. The TGF-β superfamily cytokine, MIC-1/GDF15: A pleotrophic cytokine with roles in inflammation, cancer and metabolism vol.29, pp.5, 2011,
  20. Response vol.105, pp.9, 2013,
  21. The diverse roles of nonsteroidal anti-inflammatory drug activated gene (NAG-1/GDF15) in cancer vol.85, pp.5, 2013,
  22. Nonsteroidal anti-inflammatory drug activated gene-1 (NAG-1) modulators from natural products as anti-cancer agents vol.100, pp.2, 2014,
  23. Cleavage of growth differentiation factor 15 (GDF15) by membrane type 1-matrix metalloproteinase abrogates GDF15-mediated suppression of tumor cell growth vol.98, pp.9, 2007,
  24. Activation of NAG-1 via JNK signaling revealed an isochaihulactone-triggered cell death in human LNCaP prostate cancer cells vol.11, pp.1, 2011,
  25. Prognostic and predictive value of epigenetic biomarkers and clinical factors in upper tract urothelial carcinoma vol.7, pp.5, 2015,
  26. Cyclooxygenase inhibitors induce apoptosis in sinonasal cancer cells by increased expression of nonsteroidal anti-inflammatory drug-activated gene vol.122, pp.8, 2007,
  27. Early Epithelial Restitution by Nonsteroidal Anti-Inflammatory Drug–Activated Gene 1 Counteracts Intestinal Ulcerative Injuries vol.197, pp.4, 2016,
  28. Implication of intracellular ROS formation, caspase-3 activation and Egr-1 induction in platycodon D-induced apoptosis of U937 human leukemia cells vol.63, pp.2, 2009,
  29. The H6D variant of NAG-1/GDF15 inhibits prostate xenograft growth in vivo vol.72, pp.6, 2012,
  30. Novel herbal flavonoids promote apoptosis but differentially induce cell cycle arrest in human colon cancer cell vol.28, pp.1, 2010,
  31. Anti-tumoral Effects of miR-3189-3p in Glioblastoma vol.290, pp.13, 2015,
  32. The divergent roles of growth differentiation factor-15 (GDF-15) in benign and malignant skin pathologies vol.307, pp.7, 2015,
  33. Relationship between hepcidin and GDF15 in anemic patients with type 2 diabetes without overt renal impairment vol.109, pp.1, 2015,
  34. A novel anticancer effect of Astragalus saponins: Transcriptional activation of NSAID-activated gene vol.125, pp.5, 2009,
  35. NSAIDs: Old Drugs Reveal New Anticancer Targets vol.3, pp.5, 2010,
  36. GDF15 and Growth Control vol.9, pp.1664-042X, 2018,
  37. Quercetin: A functional dietary flavonoid with potential chemo-preventive properties in colorectal cancer vol.233, pp.9, 2018,