Conjugated EPA activates mutant p53 via lipid peroxidation and induces p53-dependent apoptosis in DLD-1 colorectal adenocarcinoma human cells

摘要

Both conjugated linoleic acid (CLA), which contains conjugated double bonds, and eicosapentacnoic acid (EPA), an n-3 polyunsaturated fatty acid, have antitumor effects. Hence, we hypothesized that a combination of conjugated double bonds and an n-3 highly unsaturated fatty acid may produce a stronger antitumor effect, and we have previously shown that conjugated EPA (CEPA), prepared by alkaline treatment of EPA, induces strong and selective apoptosis in vitro and in vivo, with the mechanism proceeding via lipid peroxidation. In this study, we examined CEPA-induced gene expression in DLD-1 colorectal adenocarcinoma human cells carrying a mutant p53, in order to understand the details of CEPA-induced apoptosis via lipid peroxidation. DNA microarray analysis of 9970 genes was performed by comparison of CEPA-treated DLD-1 cells with untreated DLD-1 cells, thereby allowing determination of the differential gene expression profile induced by CEPA in these cells. CEPA treatment caused up-regulation of expression of genes induced by p53 and activation of the mitochondrial apoptosis pathway via Bax and the death pathway via TRAIL, leading to apoptosis of DLD-1 cells. In addition, activation of the mutant p53 was also induced by CEPA, and these effects showed lipid-peroxidation dependency. This is the first such gene expression analysis of the effects of CEPA, and our results confirm that CEPA induces lipid peroxidation, activates mutant p53, and causes p53-dependent apoptosis in DLD-1 cells. (c) 2006 Elsevier B.V. All rights reserved.