Abstract
The mechanisms underlying the anti-tumorigenic properties of cyclooxygenase inhibitors are not well understood. One novel hypothesis is alterations in gene expression. To test this hypothesis sulindac sulfide, which is used to treat familial adenomatous polyposis, was selected to detect gene modulation in human colorectal cells at physiological concentrations with microarray analysis. At micromolar concentrations, sulindac sulfide stimulated apoptosis and inhibited the growth of colorectal cancer cells on soft agar. Sulindac sulfide (10 microm) altered the expression of 65 genes in SW-480 colorectal cancer cells, which express cyclooxygenase-1 but little cyclooxygenase-2. A more detailed study of 11 genes revealed that their expression was altered in a time- and dose-dependent manner as measured by real-time RT-PCR. Northern analysis confirmed the expression of 9 of these genes, and Western analysis supported the conclusion that sulindac sulfide altered the expression of these proteins. Cyclooxygenase-deficient HCT-116 cells were more responsive to sulindac sulfide-induced gene expression than SW-480 cells. However, this response was diminished in HCT-116 cells overexpressing cyclooxygenase-1 compared with normal HCT-116 cells suggesting the presence of cyclooxygenase attenuates this response. However, prostaglandin E2, the main product of cyclooxygenase, only suppressed the sulindac sulfide-induced expression of two genes, with little known biological function while it modulated the expression of two more. The most likely explanation for this finding is the metabolism of sulindac sulfide to inactive metabolites by the peroxidase activity of cyclooxygenase. In conclusion, this is the first report showing sulindac sulfide, independent of cyclooxygenase, altered the expression of several genes possibly linked to its anti-tumorigenic and pro-apoptotic activity.
Highlights
The mechanisms underlying the anti-tumorigenic Colorectal cancer is the third leading cancer in the United properties of cyclooxygenase inhibitors are not well un- States
Prostaglandin E2, the main product of cyclooxygenase, only suppressed the sulindac sulfide-induced expression of animal studies, and in vitro studies with human colorectal carcinoma cells indicate that non-steroidal anti-inflammatory drugs (NSAIDs)1 such as sulindac have anti-tumorigenic activity directed against colorectal cancer [1,2,3,4]
Comparison of Gene Expression in Normal versus Tumor Tissue—Msh homeo box homolog 1 (MSX1) and MAD2 are repressed by sulindac sulfide, whereas C/EBP and Activating transcription factor 3 (ATF3) are linked to apoptosis and are highly induced by sulindac sulfide, and these are the only genes with commercially available antibodies at the time of this study
Summary
The most likely explanation for this finding is the metabolism of sulindac sulfide to inactive metabolites by the peroxidase activity of cyclooxygenase This is the first report showing sulindac sulfide, independent of cyclooxygenase, altered the expression of several genes possibly linked to its anti-tumorigenic and pro-apoptotic activity. NAG-1 has potent anti-tumorigenic activity as overexpression of NAG-1 induces apoptosis in cultured cells and suppresses xenograft growth in nude mice [25], it is likely only one of several genes involved in the pro-apoptotic and anti-tumorigenic effects of sulindac sulfide. We report here that sulindac sulfide increases and represses the expression of a number of genes with potential responsibility for the pro-apoptotic, antitumorigenic activity of sulindac sulfide This is the first report showing alterations in gene expression in colorectal cancer cells at physiological concentrations of NSAIDs using microarray technology
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