TOPOISOMERASE-II INHIBITION DIFFERENTIALLY MODULATES CACO-2 INTESTINAL EPITHELIAL-CELL PHENOTYPE

Caco-2 intestinal epithelial cells differentiate spontaneously after c onfluence when contact inhibition slows proliferation. We hypothesized that such reversible differentiation might be dependent on DNA synthe sis and repair. We studied the effects of the topoisomerase II inhibit or etoposide on Caco-2 proliferation and on the differentiation marker s alkaline phosphatase and dipeptidyl dipeptidase specific activity, a s well cell motility. Etoposide (0.3-10 mu M) dose-dependently inhibit ed proliferation and alkaline phosphatase activity. However, etoposide (0.7-3 mu M) dose-dependently stimulated dipeptidyl dipeptidase activ ity. Above this concentration, dipeptidyl dipeptidase was also inhibit ed. Similar effects on enzyme activity were observed when proliferatio n was blocked with mitomycin C. Etoposide (1-10 mu M) alo dose-depende ntly inhibited cell motility. The selective stimulation of dipeptidyl dipeptidase activity by etoposide may offer a clue to the regulation o f intestinal brush border enzyme expression at the molecular level. (C ) 1996 Academic Press, Inc.