NSAID Activated Gene (NAG-1), a Modulator of Tumorigenesis
Thomas E. Eling1,*, Seung Joon Baek2, Minsub Shim1 and Chang Ho Lee3
1National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709, USA
2Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA
3Department of Biology, Kangnung National University, 210-702, Korea
The NSAID activated gene (NAG-1), a member of the TGF-β 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-β 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-3β pathway, suggesting NAG-1 alters cell survival. Thus, NAG-1 expression is regulated by tumor suppressor pathways and appears to modulate tumor progression.