Endothelin-receptor antagonists are proapoptotic and antiproliferative in human colon cancer cells.
Endothelin (ET)-1 can act as an autocrine/paracrine growth factor or an antiapoptotic factor in human cancers. To study the role of ET-1 in human colon cancer, proliferation and apoptosis of colon carcinoma cells was investigated using human HT-29 and SW480 colon carcinoma cells. ET-1 was secreted by these cells. Treatment of cells with bosentan, a dual ET(A/B)-receptor antagonist, decreased cell number. Inhibition of DNA synthesis by bosentan was observed only in the presence of serum. Exogenously added ET-1 did not increase DNA synthesis in serum-deprived cells. SW480 cells were sensitive and HT-29 cells were resistant to FasL-induced apoptosis. Bosentan sensitised resistant HT-29 cells to FasL-induced, caspase-mediated apoptosis, but not to TNF-alpha-induced apoptosis. Bosentan and/or FasLigand (FasL) did not modulate the expression of caspase-8 or FLIP. Bosentan sensitisation to apoptosis was reversed by low concentrations (10(-13)-10(-10) M), but not by high concentrations (10(-9)-10(-7) M) of ET-1. These results suggest that the binding of ET-1 to high-affinity sites inhibits FasL-induced apoptosis, while the binding of either ET-1 or receptor antagonists to low-affinity sites promotes FasL-induced apoptosis. In conclusion, endothelin signalling pathways do not induce human colon cancer cell proliferation, but are survival signals controling resistance to apoptosis.
Peduto Eberl
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University Institute of Pathology, CHUV, University of Lausanne, Bugnon 25, Switzerland.
Bovey
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Juillerat-Jeanneret
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D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D000077300:Bosentan; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017931:DNA Primers; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*
D017931:DNA Primers; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D013449:Sulfonamides; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D000077300:Bosentan