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.
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
Sumayah
S
Jamal
Robert J
RJ
Schneider
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