BACKGROUND: Butyrate, a potent histone deacetylase inhibitor, belongs to a promising new class of antineoplastic agents with the capacity to induce apoptosis of cancer cells. However, the underlying mechanisms of action have yet not been elucidated. AIM: To further investigate the molecular events involved in butyrate-induced caspase-3 activation in Caco-2 wild-type, empty-vector and dominant-negative PPARgamma mutant cells along the signalling pathway. In this context, the involvement and up-regulation of PPARgamma was examined. RESULTS: Stimulation of cells with butyrate resulted in increased expression of PPARgamma mRNA, protein, and activity as well as phospho-p38 MAPK protein expression and caspase-3 activity. Arsenite, a direct stimulator of p38 MAPK, also led to an increased PPARgamma expression, thereby mimicking the effects of butyrate. In contrast, butyrate-mediated up-regulation of PPARgamma was counteracted by co-incubation with the p38 MAPK inhibitor SB203580. Treatment of cells with butyrate resulted in both increased caspase-8 and -9 activity and reduced expression of XIAP and survivin. However, butyrate-mediated effects on these apoptosis-regulatory proteins leading to caspase-3 activation were almost completely abolished in Caco-2 dominant-negative PPARgamma mutant cells. CONCLUSIONS: Our data clearly unveil PPARgamma as a key target in the butyrate-induced signalling cascade leading to apoptosis via caspase-3 in Caco-2 cells.
BACKGROUND:Butyrate, a potent histone deacetylase inhibitor, belongs to a promising new class of antineoplastic agents with the capacity to induce apoptosis of cancer cells. However, the underlying mechanisms of action have yet not been elucidated. AIM: To further investigate the molecular events involved in butyrate-induced caspase-3 activation in Caco-2 wild-type, empty-vector and dominant-negative PPARgamma mutant cells along the signalling pathway. In this context, the involvement and up-regulation of PPARgamma was examined. RESULTS: Stimulation of cells with butyrate resulted in increased expression of PPARgamma mRNA, protein, and activity as well as phospho-p38 MAPK protein expression and caspase-3 activity. Arsenite, a direct stimulator of p38 MAPK, also led to an increased PPARgamma expression, thereby mimicking the effects of butyrate. In contrast, butyrate-mediated up-regulation of PPARgamma was counteracted by co-incubation with the p38 MAPK inhibitor SB203580. Treatment of cells with butyrate resulted in both increased caspase-8 and -9 activity and reduced expression of XIAP and survivin. However, butyrate-mediated effects on these apoptosis-regulatory proteins leading to caspase-3 activation were almost completely abolished in Caco-2 dominant-negative PPARgamma mutant cells. CONCLUSIONS: Our data clearly unveil PPARgamma as a key target in the butyrate-induced signalling cascade leading to apoptosis via caspase-3 in Caco-2 cells.
Authors: Markus Schwab; Veerle Reynders; Stefan Loitsch; Dieter Steinhilber; Oliver Schröder; Jürgen Stein Journal: Immunology Date: 2008-03-27 Impact factor: 7.397