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Endothelin-receptor antagonists are proapoptotic and antiproliferative in human colon cancer cells.

Peduto Eberl L, Bovey R, Juillerat-Jeanneret L - Br. J. Cancer (2003)

Bottom Line: Bosentan and/or FasLigand (FasL) did not modulate the expression of caspase-8 or FLIP.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.

View Article: PubMed Central - PubMed

Affiliation: University Institute of Pathology, CHUV, University of Lausanne, Bugnon 25, Switzerland.

ABSTRACT
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.

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Low concentrations of exogenous ET-1 antagonises and high concentrations of ET-1 promotes bosentan-induced apoptosis. (A) Low concentrations of exogenous ET-1 antagonises bosentan-induced apoptosis (apoptosis index=1 in the absence of bosentan, FasL and ET-1) in HT-29 cells. Half-confluent human HT-29 colon carcinoma cells were incubated simultaneously with bosentan (80 μM), FasL and increasing concentrations of ET-1 (10−13–10−10 M). Apoptosis was evaluated after 24 h of incubation. (B) High concentrations of ET-1 promotes apoptosis (apoptosis index=1 in the presence of bosentan and FasL, without ET-1). Half-confluent human HT-29 (▪) or rat PROb (▴) and REGb (♦) colon carcinoma cells were incubated simultaneously with bosentan (80 μM for HT-29 cells; or 25 μM for PROb and REGb cells), FasL and increasing concentrations of ET-1 (10−13–10−7 M). Apoptosis was evaluated after 24 h of incubation. Means+s.d. were calculated. One representative experiment out of three is shown.
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fig6: Low concentrations of exogenous ET-1 antagonises and high concentrations of ET-1 promotes bosentan-induced apoptosis. (A) Low concentrations of exogenous ET-1 antagonises bosentan-induced apoptosis (apoptosis index=1 in the absence of bosentan, FasL and ET-1) in HT-29 cells. Half-confluent human HT-29 colon carcinoma cells were incubated simultaneously with bosentan (80 μM), FasL and increasing concentrations of ET-1 (10−13–10−10 M). Apoptosis was evaluated after 24 h of incubation. (B) High concentrations of ET-1 promotes apoptosis (apoptosis index=1 in the presence of bosentan and FasL, without ET-1). Half-confluent human HT-29 (▪) or rat PROb (▴) and REGb (♦) colon carcinoma cells were incubated simultaneously with bosentan (80 μM for HT-29 cells; or 25 μM for PROb and REGb cells), FasL and increasing concentrations of ET-1 (10−13–10−7 M). Apoptosis was evaluated after 24 h of incubation. Means+s.d. were calculated. One representative experiment out of three is shown.

Mentions: Addition of low concentrations of exogenous ET-1 (10−13–10−10 M) to HT-29 cells together with 80 μM bosentan and FasL antagonised bosentan sensitisation to FasL-induced apoptosis (Figure 6AFigure 6


Endothelin-receptor antagonists are proapoptotic and antiproliferative in human colon cancer cells.

Peduto Eberl L, Bovey R, Juillerat-Jeanneret L - Br. J. Cancer (2003)

Low concentrations of exogenous ET-1 antagonises and high concentrations of ET-1 promotes bosentan-induced apoptosis. (A) Low concentrations of exogenous ET-1 antagonises bosentan-induced apoptosis (apoptosis index=1 in the absence of bosentan, FasL and ET-1) in HT-29 cells. Half-confluent human HT-29 colon carcinoma cells were incubated simultaneously with bosentan (80 μM), FasL and increasing concentrations of ET-1 (10−13–10−10 M). Apoptosis was evaluated after 24 h of incubation. (B) High concentrations of ET-1 promotes apoptosis (apoptosis index=1 in the presence of bosentan and FasL, without ET-1). Half-confluent human HT-29 (▪) or rat PROb (▴) and REGb (♦) colon carcinoma cells were incubated simultaneously with bosentan (80 μM for HT-29 cells; or 25 μM for PROb and REGb cells), FasL and increasing concentrations of ET-1 (10−13–10−7 M). Apoptosis was evaluated after 24 h of incubation. Means+s.d. were calculated. One representative experiment out of three is shown.
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Related In: Results  -  Collection

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fig6: Low concentrations of exogenous ET-1 antagonises and high concentrations of ET-1 promotes bosentan-induced apoptosis. (A) Low concentrations of exogenous ET-1 antagonises bosentan-induced apoptosis (apoptosis index=1 in the absence of bosentan, FasL and ET-1) in HT-29 cells. Half-confluent human HT-29 colon carcinoma cells were incubated simultaneously with bosentan (80 μM), FasL and increasing concentrations of ET-1 (10−13–10−10 M). Apoptosis was evaluated after 24 h of incubation. (B) High concentrations of ET-1 promotes apoptosis (apoptosis index=1 in the presence of bosentan and FasL, without ET-1). Half-confluent human HT-29 (▪) or rat PROb (▴) and REGb (♦) colon carcinoma cells were incubated simultaneously with bosentan (80 μM for HT-29 cells; or 25 μM for PROb and REGb cells), FasL and increasing concentrations of ET-1 (10−13–10−7 M). Apoptosis was evaluated after 24 h of incubation. Means+s.d. were calculated. One representative experiment out of three is shown.
Mentions: Addition of low concentrations of exogenous ET-1 (10−13–10−10 M) to HT-29 cells together with 80 μM bosentan and FasL antagonised bosentan sensitisation to FasL-induced apoptosis (Figure 6AFigure 6

Bottom Line: Bosentan and/or FasLigand (FasL) did not modulate the expression of caspase-8 or FLIP.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.

View Article: PubMed Central - PubMed

Affiliation: University Institute of Pathology, CHUV, University of Lausanne, Bugnon 25, Switzerland.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus