Butyrate-induced differentiation of Caco-2 cells is mediated by vitamin D receptor

Butyrate in combination with 1,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] produces a synergistic effect on cell differentiation of human colon cancer cells (Caco-2). The objective of this study was to confirm the role of the vitamin D receptor (VDR) in butyrate-induced cell differentiation of Caco-2. We studied the effects of the novel VDR antagonist ZK 191732 on butyrate-induced cell differentiation and on p21(Waf1/Cip1) expression. Butyrate induced cell differentiation which was further enhanced after addition of 1,25-(OH)2D3. Experiments using ZK 191732 indicate that the synergistic effect of butyrate and 1,25-(OH)2D3 was due to butyrate-induced upregulation of VDR. While butyrate alone increased expression of p21(Waf1/Cip1) and combined exposure of butyrate and 1,25-(OH)2D3 resulted in a synergistic amplification, p21(Waf1/Cip1) expression did not change from the control level after treatment with butyrate plus ZK 191732. These data further imply that butyrate-induced differentiation and p21(Waf1/Cip1) expression of Caco-2 cells occur via upregulation of VDR. (C) 2001 Academic Press.