Induction of spermidine/spermine N1-acetyltransferase (SSAT) by aspirin in Caco-2 colon cancer cells

Epidemiological, experimental and clinical results suggest that aspirin AND other NSAIDs (non-steroidal anti-inflammatory drugs) inhibit the development of colon cancer. It has been shown that the NSAID sulindac induces apoptosis and Suppresses carcinogenesis, in part, by a mechanism leading to the transcriptional activation of the gene encoding SSAT (spermdine/spermine N-1-acetyltransferase), a rate-limiting enzyme in polyamine catabolism. In the present Study, we show that a variety of NSAIDs, including aspirin, sulindac, ibuprofen and indomethacin, call induce SSAT gene expression in Caco-2 cells. Aspirin, at physiological concentrations, call induce SSAT mRNA via transcriptional initiation mechanisms. This induction leads to increased SSAT protein levels and enzyme activity. Promoter deletion analysis of the 5' SSAT promoter-flanking region led to the identification of two NF-kappa B (nuclear factor kappa B) response elements. Electrophoretic mobillity-shift assays showed binding of NF-kappa B complexes at these sequences after-aspirin treatment. Aspirin treatment led to the activation of NF-kappa B signalling and increased binding at these NF-kappa B sites in the SSAT promoter, hence providing a potential mechanism for the induction of SSAT by aspirin in these cells. Aspirin-induced SSAT ultimately leads to a decrease in Cellular-polyamine content, which has been associated with decreased carcinogenesis. These results suggest that activation of SSAT by aspirin and different NSAIDs may be a common property of NSAIDs that plays all important role in their chemopreventive actions in colorectal cancer.