Endothelin receptor blockade potentiates FasL-induced apoptosis in rat colon carcinoma cells.
Imbalanced proliferation and apoptosis is important in tumor progression. Endothelin (ET)-1, a 21-amino-acid peptide with vasoconstricting and mitogenic activities, has been shown to be involved in the regulation of apoptosis. Progressive and regressive rat colon (PROb and REGb cells) carcinoma cell lines express the components of the ET-1 system (preproET-1, ET-converting enzyme and ET-receptors) and secrete ET-1. These cells also express the Fas(APO-1, CD95)/FasL system, but are resistant to FasL-induced apoptosis. We thus addressed the role of ET-1 in FasL-dependent cell death. Bosentan, a mixed ET(A)/ET(B) receptor antagonist, potentiated FasL-induced apoptosis in these cells. At low concentrations (10(-13) to 10(-10) M), ET-1 dose-dependently reversed bosentan-induced apoptosis. Bosentan sensitization to FasL-induced apoptosis was not mediated by increased expression of Fas receptor and was blocked by the caspase inhibitor zVAD-fmk. The specific inhibition of enzymes involved in ceramide production did not restore survival of cells exposed to FasL and bosentan. Our results suggest that ET-1 is a survival factor able to protect in vitro colon carcinoma cells against FasL-induced apoptosis.
Eberl
L P
LP
Institute of Pathology, University of Lausanne, Lausanne, Switzerland.
Valdenaire
O
O
Saintgiorgio
V
V
Jeannin
J F
JF
Juillerat-Jeanneret
L
L
D000230:Adenocarcinoma / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D016282:Aspartic Acid Endopeptidases / Q000235:genetics; D000077300:Bosentan; D061945:Caspase Inhibitors; D003110:Colonic Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D004357:Drug Synergism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000502:physiology; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology* / Q000502:physiology; D008666:Metalloendopeptidases; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017466:Receptors, Endothelin / Q000235:genetics / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000096:biosynthesis
D061945:Caspase Inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D011498:Protein Precursors; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D013449:Sulfonamides; D019014:fas Receptor; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D000077300:Bosentan