title: A zebrafish chemical suppressor screening identifies small molecule inhibitors of the Wnt/β-catenin pathway.
abstract: Genetic screening for suppressor mutants has been successfully used to identify important signaling regulators. Using an analogy to genetic suppressor screening, we developed a chemical suppressor screening method to identify inhibitors of the Wnt/β-catenin signaling pathway. We used zebrafish embryos in which chemically induced β-catenin accumulation led to an "eyeless" phenotype and conducted a pilot screening for compounds that restored eye development. This approach allowed us to identify geranylgeranyltransferase inhibitor 286 (GGTI-286), a geranylgeranyltransferase (GGTase) inhibitor. Our follow-up studies showed that GGTI-286 reduces nuclear localization of β-catenin and transcription dependent on β-catenin/T cell factor in mammalian cells. In addition to pharmacological inhibition, GGTase gene knockdown also attenuates the nuclear function of β-catenin. Overall, we validate our chemical suppressor screening as a method for identifying Wnt/β-catenin pathway inhibitors and implicate GGTase as a potential therapeutic target for Wnt-activated cancers.
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmacy, Yahaba, Iwate 028-3694, Japan. Electronic address: nnishiya@iwate-med.ac.jp.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Nishiya
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmacy, Yahaba, Iwate 028-3694, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Oku
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmacy, Yahaba, Iwate 028-3694, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kumagai
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmacy, Yahaba, Iwate 028-3694, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmacy, Yahaba, Iwate 028-3694, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Yamaguchi
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmacy, Yahaba, Iwate 028-3694, Japan.
authors.forename: Akari
authors.initials: A
authors.lastname: Sasaki
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmacy, Yahaba, Iwate 028-3694, Japan.
authors.forename: Momoko
authors.initials: M
authors.lastname: Shoji
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmacy, Yahaba, Iwate 028-3694, Japan.
authors.forename: Yukimi
authors.initials: Y
authors.lastname: Ohnishi
authors.affiliation: Laboratory for Developmental Gene Regulation, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okamoto
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmacy, Yahaba, Iwate 028-3694, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Uehara
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005123:Eye / Q000187:drug effects / Q000254:growth & development; D007930:Leucine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D015027:Zebrafish / Q000033:anatomy & histology / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C437105:GGTI 286; D054852:Small Molecule Libraries; D051153:Wnt Proteins; D051176:beta Catenin; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D007930:Leucine