Hahn, Heidi Eva

[["dc.bibliographiccitation.firstpage","8722"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Oncotarget"],["dc.bibliographiccitation.lastpage","8735"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Graab, Ulrike"],["dc.contributor.author","Hahn, Heidi"],["dc.contributor.author","Fulda, Simone"],["dc.date.accessioned","2019-07-09T11:42:39Z"],["dc.date.available","2019-07-09T11:42:39Z"],["dc.date.issued","2015-04-20"],["dc.description.abstract","We previously reported that aberrant HH pathway activation confers a poor prognosis in rhabdomyosarcoma (RMS). Searching for new treatment strategies we therefore targeted HH signaling. Here, we identify a novel synthetic lethality of concomitant inhibition of HH and PI3K/AKT/mTOR pathways in RMS by GLI1/2 inhibitor GANT61 and PI3K/mTOR inhibitor PI103. Synergistic drug interaction is confirmed by calculation of combination index (CI < 0.2). Similarly, genetic silencing of GLI1/2 significantly increases PI103-induced apoptosis. GANT61 and PI103 also synergize to induce apoptosis in cultured primary RMS cells emphasizing the clinical relevance of this combination. Importantly, GANT61/PI103 cotreatment suppresses clonogenic survival, three-dimensional sphere formation and tumor growth in an in vivo model of RMS. Mechanistic studies reveal that GANT61 and PI103 cooperate to trigger caspase-dependent apoptosis via the mitochondrial pathway, as demonstrated by several lines of evidence. First, GANT61/PI103 cotreatment increases mRNA and protein expression of NOXA and BMF, which is required for apoptosis, since knockdown of NOXA or BMF significantly reduces GANT61/PI103-induced apoptosis. Second, GANT61/PI103 cotreatment triggers BAK/BAX activation, which contributes to GANT61/PI103-mediated apoptosis, since knockdown of BAK provides protection. Third, ectopic expression of BCL-2 or non-degradable phospho-mutant MCL-1 significantly rescue GANT61/PI103-triggered apoptosis. Fourth, GANT61/PI103 cotreatment initiate activation of the caspase cascade via apoptosome-mediated cleavage of the initiator caspase-9, as indicated by changes in the cleavage pattern of caspases (e.g. accumulation of the caspase-9 p35 cleavage fragment) upon addition of the caspase inhibitor zVAD.fmk. Thus, combined GLI1/2 and PI3K/mTOR inhibition represents a promising novel approach for synergistic apoptosis induction and tumor growth reduction with implications for new treatment strategies in RMS."],["dc.identifier.doi","10.18632/oncotarget.2726"],["dc.identifier.fs","613066"],["dc.identifier.pmid","25749378"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13615"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/58714"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","1949-2553"],["dc.rights","CC BY 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/3.0"],["dc.subject.mesh","Amino Acid Chloromethyl Ketones"],["dc.subject.mesh","Animals"],["dc.subject.mesh","Apoptosis"],["dc.subject.mesh","Apoptosis Regulatory Proteins"],["dc.subject.mesh","Caspases"],["dc.subject.mesh","Cell Line, Tumor"],["dc.subject.mesh","Chick Embryo"],["dc.subject.mesh","Drug Screening Assays, Antitumor"],["dc.subject.mesh","Drug Synergism"],["dc.subject.mesh","Furans"],["dc.subject.mesh","Gene Expression Regulation, Neoplastic"],["dc.subject.mesh","Hedgehog Proteins"],["dc.subject.mesh","Humans"],["dc.subject.mesh","Kruppel-Like Transcription Factors"],["dc.subject.mesh","Molecular Targeted Therapy"],["dc.subject.mesh","Neoplasm Proteins"],["dc.subject.mesh","Nuclear Proteins"],["dc.subject.mesh","Phosphatidylinositol 3-Kinases"],["dc.subject.mesh","Protein Kinase Inhibitors"],["dc.subject.mesh","Proto-Oncogene Proteins c-akt"],["dc.subject.mesh","Pyridines"],["dc.subject.mesh","Pyrimidines"],["dc.subject.mesh","Rhabdomyosarcoma, Alveolar"],["dc.subject.mesh","Rhabdomyosarcoma, Embryonal"],["dc.subject.mesh","Signal Transduction"],["dc.subject.mesh","TOR Serine-Threonine Kinases"],["dc.subject.mesh","Transcription Factors"],["dc.title","Identification of a novel synthetic lethality of combined inhibition of hedgehog and PI3K signaling in rhabdomyosarcoma."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]