Anti-carcinogenic Activity--Nsaids Mediated By New Tgf-b

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Non-steroidal anti-inflammatory drugs (NSAIDs) are used for the treatment of inflammatory diseases. Recently, NSAIDs have been reported to have chemopreventive effects on the development of human colorectal cancer. NSAIDs can inhibit COX-1 and/or COX-2 activity and thus inhibit prostaglandin synthesis. However, some reports indicate that the chemopreventive effect on colon cancer may, in part, be independent of prostaglandin inhibition could dependent on gene expression. Our goal is to identify and characterize genes that are regulated by Cox inhibitors including selective Cox inhibitors. In our first attempt to identify Cox regulated genes we used a PCR based method. Treatment of human colon cancer cells as well as breast and lung cancer cells with NSAIDs caused the up-regulation of novel gene (NAG-1, "NSAIDs activated gene") that we have characterized as member of the TGF-b superfamily gene. The project has with three primary aims; 1) to further characterize the expression of NAG-1 by NSAIDs and to explore the potential down regulation by pro-inflammatory agents, 2) to investigate the transacting elements in the NAG-1 gene promoter, and 3) to identify biological function(s) of NAG-1 protein in apoptosis and inflammation using cell culture and animal models. In addition, we have also used Microarray technology to identify genes regulated by Cox inhibitors and have found a number of genes that are induced and suppressed. For example the expression ATF3, TSP-1 and laminin are altered by Cox inhibitor and these proteins have biological activities associated with the biological activity of NSAIDs. These studies may provide new insights and mechanisms for the attenuation of colon cancer and anti-inflammatory activity of NSAIDs.