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

Br J Cancer. 2003 Mar 10;88(5):788-95. doi: 10.1038/sj.bjc.6600810.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Base Sequence
  • Bosentan
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism
  • Cell Division / drug effects*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • DNA Primers
  • Endothelin Receptor Antagonists*
  • Endothelin-1 / metabolism
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sulfonamides / pharmacology*

Substances

  • DNA Primers
  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Sulfonamides
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9
  • Caspases
  • Bosentan