title: Identification and characterization of a small-molecule inhibitor of Wnt signaling in glioblastoma cells.
abstract: Glioblastoma multiforme (GBM) is the most common and prognostically unfavorable form of brain tumor. The aggressive and highly invasive phenotype of these tumors makes them among the most anatomically damaging human cancers with a median survival of less than 1 year. Although canonical Wnt pathway activation in cancers has been historically linked to the presence of mutations involving key components of the pathway (APC, β-catenin, or Axin proteins), an increasing number of studies suggest that elevated Wnt signaling in GBM is initiated by several alternative mechanisms that are involved in different steps of the disease. Therefore, inhibition of Wnt signaling may represent a therapeutically relevant approach for GBM treatment. After the selection of a GBM cell model responsive to Wnt inhibition, we set out to develop a screening approach for the identification of compounds capable of modulating canonical Wnt signaling and associated proliferative responses in GBM cells. Here, we show that the small molecule SEN461 inhibits the canonical Wnt signaling pathway in GBM cells, with relevant effects at both molecular and phenotypic levels in vitro and in vivo. These include SEN461-induced Axin stabilization, increased β-catenin phosphorylation/degradation, and inhibition of anchorage-independent growth of human GBM cell lines and patient-derived primary tumor cells in vitro. Moreover, in vivo administration of SEN461 antagonized Wnt signaling in Xenopus embryos and reduced tumor growth in a GBM xenograft model. These data represent the first demonstration that small-molecule-mediated inhibition of Wnt signaling may be a potential approach for GBM therapeutics.
authors.affiliation: Corresponding Author: Massimiliano Salerno, Siena Biotech Medicine Research Centre, Via del Petriccio e Belriguardo 35, 53100, Siena, Italy. msalerno@sienabiotech.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: De Robertis
authors.forename: Silvia
authors.initials: S
authors.lastname: Valensin
authors.forename: Marco
authors.initials: M
authors.lastname: Rossi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Tunici
authors.forename: Margherita
authors.initials: M
authors.lastname: Verani
authors.forename: Antonella
authors.initials: A
authors.lastname: De Rosa
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giordano
authors.forename: Maurizio
authors.initials: M
authors.lastname: Varrone
authors.forename: Arianna
authors.initials: A
authors.lastname: Nencini
authors.forename: Carmela
authors.initials: C
authors.lastname: Pratelli
authors.forename: Tiziana
authors.initials: T
authors.lastname: Benicchi
authors.forename: Annette
authors.initials: A
authors.lastname: Bakker
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hill
authors.forename: Kanda
authors.initials: K
authors.lastname: Sangthongpitag
authors.forename: Vishal
authors.initials: V
authors.lastname: Pendharkar
authors.forename: Boping
authors.initials: B
authors.lastname: Liu
authors.forename: Fui Mee
authors.initials: FM
authors.lastname: Ng
authors.forename: Siew Wen
authors.initials: SW
authors.lastname: Then
authors.forename: Shi
authors.initials: S
authors.lastname: Jing Tai
authors.forename: Seong-Moon
authors.initials: SM
authors.lastname: Cheong
authors.forename: Xi
authors.initials: X
authors.lastname: He
authors.forename: Andrea
authors.initials: A
authors.lastname: Caricasole
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Salerno
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011379:Prognosis; D015398:Signal Transduction; D014162:Transfection; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D014981:Xenopus
chemical_list: D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C544261:XAV939