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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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Role of bosentan and ET-1 in HT-29 and SW480 serum-deprived cells. Cells were grown to half-confluence, deprived of FCS, then bosentan or ET-1 were added for 24 h. Either MTT assay was performed or [3H]thymidine was added for the last 3 h of incubation to quantitate alive cell number or DNA synthesis, respectively. (A) ET-1 does not increase the number of metabolically active cells quantified using an MTT assay. (B) ET-1 does not induce DNA synthesis in HT-29 and SW480 cells. Grey bars: HT-29 cells, black bars: SW480 cells. (C) Bosentan decreases metabolically active cell number quantified using an MTT assay, HT-29 cells (♦), SW480 cells (□). (D) Bosentan does not inhibit DNA synthesis. White bars: no bosentan, grey bars: 10 μM bosentan; black bars: 80 μM bosentan. Experiments were repeated three times with identical information.
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fig2: Role of bosentan and ET-1 in HT-29 and SW480 serum-deprived cells. Cells were grown to half-confluence, deprived of FCS, then bosentan or ET-1 were added for 24 h. Either MTT assay was performed or [3H]thymidine was added for the last 3 h of incubation to quantitate alive cell number or DNA synthesis, respectively. (A) ET-1 does not increase the number of metabolically active cells quantified using an MTT assay. (B) ET-1 does not induce DNA synthesis in HT-29 and SW480 cells. Grey bars: HT-29 cells, black bars: SW480 cells. (C) Bosentan decreases metabolically active cell number quantified using an MTT assay, HT-29 cells (♦), SW480 cells (□). (D) Bosentan does not inhibit DNA synthesis. White bars: no bosentan, grey bars: 10 μM bosentan; black bars: 80 μM bosentan. Experiments were repeated three times with identical information.

Mentions: In serum-deprived colon carcinoma cells, ET-1 did not induce cell proliferation as determined either by MTT reduction, labelling metabolically active cells (Figure 2AFigure 2


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

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

Role of bosentan and ET-1 in HT-29 and SW480 serum-deprived cells. Cells were grown to half-confluence, deprived of FCS, then bosentan or ET-1 were added for 24 h. Either MTT assay was performed or [3H]thymidine was added for the last 3 h of incubation to quantitate alive cell number or DNA synthesis, respectively. (A) ET-1 does not increase the number of metabolically active cells quantified using an MTT assay. (B) ET-1 does not induce DNA synthesis in HT-29 and SW480 cells. Grey bars: HT-29 cells, black bars: SW480 cells. (C) Bosentan decreases metabolically active cell number quantified using an MTT assay, HT-29 cells (♦), SW480 cells (□). (D) Bosentan does not inhibit DNA synthesis. White bars: no bosentan, grey bars: 10 μM bosentan; black bars: 80 μM bosentan. Experiments were repeated three times with identical information.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376352&req=5

fig2: Role of bosentan and ET-1 in HT-29 and SW480 serum-deprived cells. Cells were grown to half-confluence, deprived of FCS, then bosentan or ET-1 were added for 24 h. Either MTT assay was performed or [3H]thymidine was added for the last 3 h of incubation to quantitate alive cell number or DNA synthesis, respectively. (A) ET-1 does not increase the number of metabolically active cells quantified using an MTT assay. (B) ET-1 does not induce DNA synthesis in HT-29 and SW480 cells. Grey bars: HT-29 cells, black bars: SW480 cells. (C) Bosentan decreases metabolically active cell number quantified using an MTT assay, HT-29 cells (♦), SW480 cells (□). (D) Bosentan does not inhibit DNA synthesis. White bars: no bosentan, grey bars: 10 μM bosentan; black bars: 80 μM bosentan. Experiments were repeated three times with identical information.
Mentions: In serum-deprived colon carcinoma cells, ET-1 did not induce cell proliferation as determined either by MTT reduction, labelling metabolically active cells (Figure 2AFigure 2

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