Endothelin receptor blockade potentiates FasL-induced apoptosis in colon carcinoma cells via the protein kinase C-pathway.
An imbalance between proliferation and apoptosis is important in tumor progression. Endothelin-1 (ET-1) has vasoconstricting and mitogenic activities and may be involved in apoptosis regulation. We found that ET-1 and FasL systems were colocalized in human colon tumors and that ET-1 was secreted by human (HT-29, SW480) and rat (PROb, REGb) colon carcinoma cell lines. Bosentan, a mixed endothelin-A- and -B- (ET(A)/ET(B)) receptor antagonist, potentiated FasL- (APO-1, CD95) induced apoptosis in these cells. The specific inhibition of enzymes involved in ceramide production did not restore survival of cells exposed to FasL and bosentan. Inhibition of PKC with bisindolylmaleimide IX enhanced FasL-induced apoptosis in HT-29, PROb and REGb cells in the absence of bosentan. These results suggest that ET-1 is an autocrine survival factor able to protect colon carcinoma cells against FasL-induced apoptosis, involving the protein kinase C (PKC) but not the sphingomyelin-ceramide signaling transduction pathways.
Eberl
L P
LP
Institute of Pathology, University of Lausanne, Switzerland.
Egidy
G
G
Pinet
F
F
Juillerat-Jeanneret
L
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000077300:Bosentan; D003110:Colonic Neoplasms / Q000473:pathology*; D065128:Endothelin Receptor Antagonists; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D065128:Endothelin Receptor Antagonists; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D011493:Protein Kinase C; D000077300:Bosentan