title: Chemical-genetic screen identifies riluzole as an enhancer of Wnt/β-catenin signaling in melanoma.
abstract: To identify new protein and pharmacological regulators of Wnt/β-catenin signaling, we used a cell-based reporter assay to screen a collection of 1857 human-experienced compounds for their ability to enhance activation of the β-catenin reporter by a low concentration of WNT3A. This identified 44 unique compounds, including the FDA-approved drug riluzole, which is presently in clinical trials for treating melanoma. We found that treating melanoma cells with riluzole in vitro enhances the ability of WNT3A to regulate gene expression, to promote pigmentation, and to decrease cell proliferation. Furthermore riluzole, like WNT3A, decreases metastases in a mouse melanoma model. Interestingly, siRNAs targeting the metabotropic glutamate receptor, GRM1, a reported indirect target of riluzole, enhance β-catenin signaling. The unexpected regulation of β-catenin signaling by both riluzole and GRM1 has implications for the future uses of this drug.
authors.affiliation: Howard Hughes Medical Institute, Department of Pharmacology, and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Box 357370, Seattle, WA 98195, USA.
authors.forename: Travis L
authors.initials: TL
authors.lastname: Biechele
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Camp
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Fass
authors.forename: Rima M
authors.initials: RM
authors.lastname: Kulikauskas
authors.forename: Nick C
authors.initials: NC
authors.lastname: Robin
authors.forename: Bryan D
authors.initials: BD
authors.lastname: White
authors.forename: Corinne M
authors.initials: CM
authors.lastname: Taraska
authors.forename: Erin C
authors.initials: EC
authors.lastname: Moore
authors.forename: Jeanot
authors.initials: J
authors.lastname: Muster
authors.forename: Rakesh
authors.initials: R
authors.lastname: Karmacharya
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Chien
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism; D019782:Riluzole / Q000627:therapeutic use*; D015398:Signal Transduction; D012880:Skin Pigmentation; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D018094:Receptors, Metabotropic Glutamate; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin; C104077:metabotropic glutamate receptor type 1; D019782:Riluzole