title: The tankyrase-specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines.
abstract: Wnt/β-catenin is a major regulator of stem cell self-renewal and differentiation and this signaling pathway is aberrantly activated in a several cancers, including osteosarcoma (OS). Attenuation of Wnt/β-catenin activity by tankyrase inhibitors is an appealing strategy in treatment of OS. The efficacy of the tankyrase inhibitor JW74 was evaluated in three OS cell lines (KPD, U2OS, and SaOS-2) both at the molecular and functional level. At the molecular level, JW74 induces stabilization of AXIN2, a key component of the β-catenin destruction complex, resulting in reduced levels of nuclear β-catenin. At the functional level, JW74 induces reduced cell growth in all three tested cell lines, in part due to a delay in cell cycle progression and in part due to an induction of caspase-3-mediated apoptosis. Furthermore, JW74 induces differentiation in U2OS cells, which under standard conditions are resistant to osteogenic differentiation. JW74 also enhances differentiation of OS cell lines, which do not harbor a differentiation block. Interestingly, microRNAs (miRNAs) of the let-7 family, which are known tumor suppressors and inducers of differentiation, are significantly upregulated following treatment with JW74. We demonstrate for the first time that tankyrase inhibition triggers reduced cell growth and differentiation of OS cells. This may in part be due to an induction of let-7 miRNA. The presented data open for novel therapeutic strategies in the treatment of malignant OS.
authors.affiliation: Cancer Stem Cell Innovation Centre and Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, PO Box 4953 Nydalen, Oslo, NO-0424, Norway.
authors.forename: Eva Wessel
authors.initials: EW
authors.lastname: Stratford
authors.forename: Jeanette
authors.initials: J
authors.lastname: Daffinrud
authors.forename: Else
authors.initials: E
authors.lastname: Munthe
authors.forename: Russell
authors.initials: R
authors.lastname: Castro
authors.forename: Jo
authors.initials: J
authors.lastname: Waaler
authors.forename: Stefan
authors.initials: S
authors.lastname: Krauss
authors.forename: Ola
authors.initials: O
authors.lastname: Myklebost
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D060465:Axin Signaling Complex / Q000235:genetics; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D010012:Osteogenesis / Q000235:genetics; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010069:Oxadiazoles / Q000008:administration & dosage*; D038501:Tankyrases / Q000037:antagonists & inhibitors / Q000235:genetics*; D014230:Triazoles / Q000008:administration & dosage*; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D060465:Axin Signaling Complex; D010069:Oxadiazoles; D038501:Tankyrases; D014230:Triazoles; C000593016:JW74 compound; C418109:TNKS protein, human
keywords: Differentiation; JW74; TNKS inhibitior; Wnt; let-7; osteosarcoma; tankyrase; β-catenin