Article: article from journal or magazin.
Endothelin-receptor antagonists are proapoptotic and antiproliferative in human colon cancer cells
British Journal of Cancer
PT - Journal Article PT - Research Support, Non-U.S. Gov't
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
Apoptosis/drug effects/Base Sequence/Caspase 8/Caspase 9/Caspases/metabolism/Cell Division/Colonic Neoplasms/Pathology/DNA Primers/Endothelin-1/Flow Cytometry/Humans/Immunohistochemistry/Receptors,Endothelin/antagonists & inhibitors/Reverse Transcriptase Polymerase Chain Reaction/Sulfonamides/pharmacology
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