UV-induction of keratinocyte endothelin-1 downregulates E-cadherin in melanocytes and melanoma cells

J Clin Invest. 2002 Aug;110(4):443-52. doi: 10.1172/JCI13729.

Abstract

Endothelin-1 (ET-1), a peptide that is secreted by keratinocytes in the skin in response to ultraviolet irradiation, is a ligand for the endothelin-B (ET(B)) receptor. Blockade of this receptor inhibits melanoma cell growth and induces cell death in vivo and in vitro. Additionally, ET(B) is a melanoma progression marker. These findings suggest that the ET-1/ET(B) receptor pathway contributes to melanoma development or progression. Here, we demonstrate that activation of the ET-1/ET(B) pathway downregulates E-cadherin and associated catenin proteins in human melanocytes and melanoma cells. E-cadherin is an established suppressor of melanoma cell invasion in vitro and in vivo. Downregulation of E-cadherin by ET-1/ET(B) involves the downstream activation of caspase-8 but not of distal, executioner caspases, and does not lead to apoptosis. ET-1 also induces a transient association between caspase-8 and E-cadherin:beta-catenin complexes. Hence, activation of the ET-1/ET(B) pathway promotes molecular events known to promote melanoma invasion.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cadherins / biosynthesis*
  • Caspase 8
  • Caspase 9
  • Caspase Inhibitors
  • Caspases / metabolism
  • Catenins
  • Cell Adhesion Molecules / metabolism
  • Cell Line
  • Cells, Cultured
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cytoskeletal Proteins / metabolism
  • Delta Catenin
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Endothelin-1 / biosynthesis*
  • Endothelin-1 / pharmacology
  • Humans
  • Keratinocytes / metabolism*
  • Keratinocytes / radiation effects
  • Melanocytes / drug effects
  • Melanocytes / metabolism*
  • Melanoma / metabolism*
  • Phosphoproteins / metabolism
  • Receptor, Endothelin B
  • Receptors, Endothelin / physiology
  • Trans-Activators / metabolism
  • Tumor Cells, Cultured
  • Ultraviolet Rays*
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • Cadherins
  • Caspase Inhibitors
  • Catenins
  • Cell Adhesion Molecules
  • Cysteine Proteinase Inhibitors
  • Cytoskeletal Proteins
  • Endothelin-1
  • Phosphoproteins
  • Receptor, Endothelin B
  • Receptors, Endothelin
  • Trans-Activators
  • beta Catenin
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9
  • Caspases
  • Delta Catenin