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Controlled Ribozyme Targeting Demonstrates an Antiapoptotic Effect of Carcinoembryonic Antigen in HT29 Colon Cancer Cells¹

Department of Oncology and Surgery, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007 [E. S., T. W., H-J. L., S. K., A. P., H. J.]; Department of Clinical Chemistry, University Clinic HH-Eppendorf, 20246 Hamburg, Germany [M. N.]; and Department of Pharmacology, University Hospital of Marburg, 35043 Marburg, Germany [F. C.]

Purpose: Clinical studies suggest that carcinoembryonic antigen (CEA) is associated with metastatic progression of colon cancer. However, the biological function of CEA is not well understood. We have established an approach that allows studying of CEA function within the intact pathophysiological context 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 allows regulation of CEA levels on the mRNA and protein level by 50% and enables screening analysis of CEA-mediated changes of gene expression by cDNA microarray analysis.

Results: Comprehensive analysis of 273 genes revealed that CEA affects expression 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-regulated by CEA. In parallel phenotypic studies, CEA did not affect cell cycle or proliferation rate. However, CEA significantly protected HT29 cells from undergoing apoptosis under various conditions, including confluent growth, UV light, IFN- treatment, and treatment with 5-fluorouracil.

Conclusions: Our study suggests that CEA has an important regulatory role in apoptosis, and we propose that CEA is a survival factor for colon cancer cells.

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