PPARgamma is a key target of butyrate-induced caspase-3 activation in the colorectal cancer cell line Caco-2.
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.


OBJECTIVE
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.
Schwab
Markus
M
First Department of Medicine-ZAFES, Johann Wolfgang Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Reynders
Veerle
V
Ulrich
Sandra
S
Zahn
Nadine
N
Stein
Jürgen
J
Schröder
Oliver
O
D020148:Butyric Acid / Q000494:pharmacology*; D018938:Caco-2 Cells; D053148:Caspase 3 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism* / Q000502:physiology*; D010766:Phosphorylation; D000077022:Survivin; D014162:Transfection; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D047495:PPAR gamma; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; D020148:Butyric Acid; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9