Resistance to butyrate-induced cell differentiation and apoptosis during spontaneous Caco-2 cell differentiation

Background & Alms: The short-chain fatty acid butyrate induces cell cycle a rrest, differentiation, and apoptosis in colon cancer cells, but often indu ces opposite effects in normal colonic epithelial cells, We determined whet her response to butyrate is dependent on the basal differentiation status o f colonic epithelial cells, Methods: Caco-2 cells at progressive stages of differentiation were treated with butyrate, and endpoints were measured. Re sults: Response of Caco-2 cells to butyrate was dependent on their differen tiation status, Butyrate maximally stimulated cell cycle arrest, apoptosis, alkaline phosphatase activity, transepithelial resistance, cell migration, urokinase receptor expression, and interleukin 8 secretion in undifferenti ated Caco-2 cells, whereas differentiated Caco-2 cells were essentially res istant to these effects, Consistently, butyrate selectively induced histone hyperacetylation in undifferentiated Caco-2 cells. This resistance was als o observed during HT29cl.19A cell differentiation, but not In the nondiffer entiating SW620 cell line, Finally, the rate of butyrate use significantly increased as Caco-2 cells underwent spontaneous differentiation. Conclusion s: Colonic epithelial cells become progressively more refractory to the eff ects of butyrate during absorptive cell differentiation, We postulate that this resistance is caused by the rapid use of butyrate by differentiated Ca co-2 cells, which likely results in low intracellular concentrations and su bsequently in its inability to inhibit histone deacetylase.