Molecular cancer therapeutics, 2017-09, Vol.16 (9), p.1954-1966
2017
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- Autor(en) / Beteiligte
- Titel
- Wnt/β-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor
- Ist Teil von
- Molecular cancer therapeutics, 2017-09, Vol.16 (9), p.1954-1966
- Ort / Verlag
- United States: American Association for Cancer Research Inc
- Erscheinungsjahr
- 2017
- Quelle
- EZB-FREE-00999 freely available EZB journals
- Beschreibungen/Notizen
- Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma and usually harbors either a or mutation. However, the molecular basis for tumor malignancy is not well defined. Although the Wnt/β-catenin signaling pathway is important in a variety of cancers, its role in GIST is uncertain. Through analysis of nearly 150 human GIST specimens, we found that some human GISTs expressed β-catenin and contained active, dephosphorylated nuclear β-catenin. Furthermore, advanced human GISTs expressed reduced levels of the Wnt antagonist DKK4. Accordingly, in human GIST T1 cells, Wnt stimulation increased β-catenin-mediated transcriptional activity in a reporter assay as well as transcription of the downstream target genes and In contrast, overexpression in GIST T1 cells reduced Wnt/β-catenin signaling. In addition, we showed that nuclear β-catenin stability was partially regulated by the E3 ligase COP1, as demonstrated with coimmunoprecipitation and COP1 knockdown. Three molecular inhibitors of the Wnt/β-catenin pathway demonstrated antitumor efficacy in various GIST models, both and Notably, the tankyrase inhibitor G007-LK alone had substantial activity against tumors of genetically engineered mice, and the effect was increased by the addition of the Kit inhibitor imatinib mesylate. Collectively, our findings demonstrate that Wnt/β-catenin signaling is a novel therapeutic target for selected untreated or imatinib-resistant GISTs. .
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1535-7163eISSN: 1538-8514DOI: 10.1158/1535-7163.MCT-17-0139Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5587376
- Format
- –
- Schlagworte
- Animal models, Animals, Anticancer properties, Antineoplastic Agents - pharmacology, Antitumor activity, beta Catenin - metabolism, Cell Line, Tumor, Disease Models, Animal, Gastrointestinal Stromal Tumors - drug therapy, Gastrointestinal Stromal Tumors - metabolism, Gastrointestinal Stromal Tumors - pathology, Genetic engineering, Humans, Imatinib, Imatinib Mesylate - pharmacology, Inhibitors, Intercellular Signaling Peptides and Proteins - metabolism, Malignancy, Mice, Mice, Transgenic, Molecular Targeted Therapy, Neoplasm Grading, Neoplasm Staging, Sarcoma, Signal transduction, Signaling, Transcription, Tumors, Ubiquitin-protein ligase, Ubiquitin-Protein Ligases - metabolism, Uncertainty analysis, Wnt protein, Wnt Signaling Pathway - drug effects, Wnt3A Protein - metabolism, Xenograft Model Antitumor Assays, β-catenin