title: β-Catenin signaling increases during melanoma progression and promotes tumor cell survival and chemoresistance.
abstract: Beta-catenin plays an important role in embryogenesis and carcinogenesis by controlling either cadherin-mediated cell adhesion or transcriptional activation of target gene expression. In many types of cancers nuclear translocation of beta-catenin has been observed. Our data indicate that during melanoma progression an increased dependency on the transcriptional function of beta-catenin takes place. Blockade of beta-catenin in metastatic melanoma cell lines efficiently induces apoptosis, inhibits proliferation, migration and invasion in monolayer and 3-dimensional skin reconstructs and decreases chemoresistance. In addition, subcutaneous melanoma growth in SCID mice was almost completely inhibited by an inducible beta-catenin knockdown. In contrast, the survival of benign melanocytes and primary melanoma cell lines was less affected by beta-catenin depletion. However, enhanced expression of beta-catenin in primary melanoma cell lines increased invasive capacity in vitro and tumor growth in the SCID mouse model. These data suggest that beta-catenin is an essential survival factor for metastatic melanoma cells, whereas it is dispensable for the survival of benign melanocytes and primary, non-invasive melanoma cells. Furthermore, beta-catenin increases tumorigenicity of primary melanoma cell lines. The differential requirements for beta-catenin signaling in aggressive melanoma versus benign melanocytic cells make beta-catenin a possible new target in melanoma therapy.
authors.affiliation: Division of Dermatooncology, Department of Dermatology, Eberhard-Karls-University Tübingen, Tübingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Sinnberg
authors.forename: Moritz
authors.initials: M
authors.lastname: Menzel
authors.forename: Daniel
authors.initials: D
authors.lastname: Ewerth
authors.forename: Birgit
authors.initials: B
authors.lastname: Sauer
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
authors.forename: Martin
authors.initials: M
authors.lastname: Schaller
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.forename: Birgit
authors.initials: B
authors.lastname: Schittek
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D004357:Drug Synergism; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D010569:Perylene / Q000031:analogs & derivatives / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C538949:PKF115-584; D051820:TCF Transcription Factors; D051176:beta Catenin; D010569:Perylene; D004318:Doxycycline; D002945:Cisplatin