Controlled ribozyme targeting demonstrates an antiapoptotic effect of carcinoembryonic antigen in HT29 colon cancer cells

Purpose: Clinical studies suggest that carcinoembryonic antigen (CEA) is as sociated with metastatic progression of colon cancer. However, the biologic al function of CEA is not well understood. We have established an approach that allows studying of CEA function within the intact pathophysiological c ontext of human colon cancer cells. Experimental Design: We expressed CEA-targeted ribozymes under control of a tet-off promoter system in human HT29 colon cancer cells. This approach al lows regulation of CEA levels on the mRNA and protein level by 50% and enab les screening analysis of CEA-mediated changes of gene expression by cDNA m icroarray analysis. Results: Comprehensive analysis of 273 genes revealed that CEA affects expr ession of various groups of cancer-related genes, in particular cell cycle and apoptotic genes. Although cell cycle gene expression showed a balanced bidirectional dysregulation, apoptotic genes were unidirectionally down-reg ulated by CEA, In parallel phenotypic studies, CEA did not affect cell cycl e or proliferation rate. However, CEA significantly protected HT29 cells fr om undergoing apoptosis under various conditions, including confluent growt h, UV light, IFN-gamma treatment, and treatment with 5-fluorouracil. Conclusions: Our study suggests that CEA has an important regulatory role i n apoptosis, and we propose that CEA is a survival factor for colon cancer cells.