The diverse roles of nonsteroidal anti-inflammatory drug activated gene (NAG-1/GDF15) in cancer

Abstract

Nonsteroidal anti-inflammatory drug (NSAID) activated gene-1, NAG-1, is a divergent member of the transforming growth factor-beta (TGF-β) superfamily that plays a complex but poorly understood role in several human diseases including cancer. NAG-1 expression is substantially increased during cancer development and progression especially in gastrointestinal, prostate, pancreatic, colorectal, breast, melanoma, and glioblastoma brain tumors. Aberrant increases in the serum levels of secreted NAG-1 correlate with poor prognosis and patient survival rates in some cancers. In contrast, the expression of NAG-1 is up-regulated by several tumor suppressor pathways including p53, GSK-3β, and EGR-1. NAG-1 expression is also induced by many drugs and dietary compounds which are documented to prevent the development and progression of cancer in mouse models. Studies with transgenic mice expressing human NAG-1 demonstrated that the expression of NAG-1 inhibits the development of intestinal tumors and prostate tumors in animal models. Laboratory and clinical evidence suggest that NAG-1, like other TGF-β family members, may have different or pleiotropic functions in the early and late stages of carcinogenesis. Upon understanding the molecular mechanism and function of NAG-1 during carcinogenesis, NAG-1 may serve as a potential biomarker for the diagnosis and prognosis of cancer and a therapeutic target for the inhibition and treatment of cancer development and progression.

Figure 1. Dimeric formation of mature NAG-1 and different forms of NAG-1 in cells

The pro-NAG-1 was cleaved at RXXR site and then secreted out the cells as a dimer. NAG-1 pro-peptide is also secreted out of cells.

Figure 2. Transcriptional regulation of NAG-1 by NSAIDs and dietary compounds

NAG-1 promoter contains several cis-acting and trans-acting elements. Both Sp1 and EGR-1 transcription factors have been identified to regulate the basal transcription of NAG-1. Two p53 sites that located within the -133 bp promoter play a pivotal role in dietary compound-induced NAG-1 expression.