Butyrate-induced apoptotic cascade in colonic carcinoma cells: Modulation of the beta-catenin-Tcf pathway and concordance with effects of sulindac and trichostatin a but not curcumin

Short-chain fatty acids play a critical role in colonic homeostasis because they stimulate pathways of growth arrest, differentiation, and apoptosis, These effects have been well characterized in colonic cell lines in vitro. We investigated the role of beta-catenin-Tcf signaling in these responses t o butyrate and other well-characterized inducers of apoptosis of colonic ep ithelial cells. Unlike wild-type APC, which down-regulates Tcf activity, bu tyrate, as well as sulindac and trichostatin A, all inducers of G(0)-G(1) c ell cycle arrest and apoptosis in the SW620 colonic carcinoma cell line, up -regulate Tcf activity. In contrast, structural analogues of butyrate that do not induce cell cycle arrest or apoptosis and curcumin, which stimulates G(2)-M arrest without inducing apoptosis, do not alter Tcf activity. Simil ar to the cell cycle arrest and apoptotic cascade induced by butyrate, the up-regulation of Tcf activity is dependent upon the presence of a mitochond rial membrane potential, unlike the APC-induced downregulation, which is in sensitive to collapse of the mitochondrial membrane potential. Moreover, th e butyrate-induced increase in Tcf activity, which is reflected in an incre ase in beta-catenin-Tcf complex formation, is independent of the down-regul ation caused by expression of wild-type APC. Thus, butyrate and wild-type A PC have different and independent effects on beta-catenin-Tcf signaling. Th ese data are consistent with other reports that suggest that the absence of wild-type APC, associated with the up-regulation of this signaling pathway , is linked to the probability of a colonic epithelial cell entering an apo ptotic cascade.