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

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:β-catenin complexes.Hence, activation of the ET-1/ET B pathway promotes molecular events known to promote melanoma invasion.