Abstract A133: Time-dependent gene expression changes in a human colon polyp cell line induced by a clinically relevant concentration of atorvastatin

Abstracts: Frontiers in Cancer Prevention Research 2008 A133 The identification of biomarkers for chemopreventive agent efficacy in cell cultures from relative target tissues is of great importance. We have utilized a cell line from a human precancerous colon polyp cell line, VACO-235, to evaluate the changes in gene expression following continuous exposure to a clinically relevant concentration of atorvastatin (0.3 nM). The changes were monitored relative to the time matched controls at 48 and 96 hours of continuous exposure. The total RNA was isolated from three replicate cultures for each time point and from four replicate cultures of the time matched controls. The RNA was analyzed using Affymetrix human genome U133 plus 2 arrays. The data were analyzed using Genespring GX (Agilent Technologies) software to determine agent induced changes and to determine significant changes (P< 0.05) that occurred at either 48 or 46 hours (2613 genes) or at both 48 and 96 hours (334 genes). The data were further analyzed using Ariadne Pathway Studio. A number of pathways showed responses that suggest possible changes in the regulation of proliferation and apoptosis. The tumor necrosis factor receptor superfamily, member 1a pathway also showed important changes. Caspase 3 was induced by 5.4 fold at 48 hours and 2.4 fold at 96 hours. Pak1(P21 activated kinease 1), caspase 8, caspase 2, and caspase 4 were also induced. The p38 MAP kinase pathway showed inhibition with MAP3K4 (MAP/ERK kinase kinase 4), which showed a 5 fold inhibition at 48 hours and 2 fold at 96 hours. Changes in the p38 MAP kinase pathway suggested inhibition of multiple kinase genes. As could be predicted, the most significantly modified pathway was LRP5 (low density lipoprotein receptor-related protein 5) which regulates low density lipoprotein. This finding suggests that atorvastatin was evaluated at a concentration that was similar to in vivo . Longer term exposure studies are currently underway to determine the effect of continuous atorvastatin exposure on the culture morphology and growth of VACO 235 cells. These data suggest that the use of a clinically-relevant concentration of atorvastatin can modify the expression of several key potential biomarkers for colon cancer prevention. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A133.