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 prog ression. Endothelin-1 (ET-1) has vasoconstricting and mitogenic activities and may be involved in apoptosis regulation. We found that ET-1 and FasL sy stems 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. Bosen tan, a mixed endothelin-A- and -B- (ETA/ETB) receptor antagonist, potentiat ed FasL- (APO-1, CD95) induced apoptosis in these cells. The specific inhib ition of enzymes involved in ceramide production did not restore survival o f cells exposed to FasL and bosentan. Inhibition of PKC with bisindolylmale imide IX enhanced FasL-induced apoptosis in HT-29. PROb and REGb cells in t he absence of bosentan. These results suggest that ET-1 is an autocrine sur vival factor able to protect colon carcinoma cells against Fast-induced apo ptosis, involving the protein kinase C(PKC) but not the sphingomyelin-ceram ide signaling transduction pathways.