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:beta-catenin complexes. Hence, activation of the ET-1/ET(B) pathway promotes molecular events known to promote melanoma invasion.
Jamal
Sumayah
S
The Ronald O. Perelman Department of Dermatology, and. The Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA. jamals01@popmail.med.nyu.edu
Schneider
Robert J
RJ
D015820:Cadherins / Q000096:biosynthesis*; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D051177:Catenins; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000528:radiation effects; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D051176:beta Catenin; D000095002:Delta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; D061945:Caspase Inhibitors; D051177:Catenins; D015815:Cell Adhesion Molecules; D015853:Cysteine Proteinase Inhibitors; D003598:Cytoskeletal Proteins; D019332:Endothelin-1; D010750:Phosphoproteins; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D015534:Trans-Activators; D051176:beta Catenin; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D000095002:Delta Catenin