STEADY-STATE LEVELS OF MITOCHONDRIAL MESSENGER-RNA SPECIES CHARACTERIZE A PREDOMINANT PATHWAY CULMINATING IN APOPTOSIS AND SHEDDING OF HT29HUMAN COLONIC-CARCINOMA CELLS

A differentiated human colonic epithelial cell has undergone relativel y stable molecular, biochemical, and cellular alterations resulting in the acquisition of structures, activities, and functions that charact erize it as one of at least three mature phenotypes: a columnar absorp tive, secretory, or enteroendocrine cell, We have shown previously tha t induction of HT29 cells with the short-chain fatty acid sodium butyr ate elevates alkaline phosphatase activity, a marker of the absorptive cell phenotype, and increases mitochondrial gene expression. Furtherm ore, this induction is accompanied by subsequent apoptosis and cell sh edding, In this report, we have investigated the effects of forskolin, a potent inducer of the MUC2 gene in HT29 cells, a marker of the secr etory phenotype, and have shown that neither apoptosis nor mitochondri al gene expression are significantly stimulated, Thus, differentiation along the secretory cell lineage may not play a major role in apoptos is of colonic epithelial cells. Moreover, we have also investigated tw o polar solvents, DMSO and dimethylformamide, which have been reported to induce a more differentiated, but as yet not well characterized, p henotype in colonic carcinoma cells in culture, Although neither polar solvent induces alkaline phosphatase expression or MUC2 expression, b oth induce significant apoptosis, again associated with significant el evation of mitochondrial gene expression. Thus, elevation of mitochond rial gene expression appears to be an important pathway in the inducti on of apoptosis in colonic epithelial cells in culture, whether or not markers characteristic of differentiation along either the absorptive or secretory cell lineage are induced.