High-Throughput Drug Screening Identifies a Potent Wnt Inhibitor that Promotes Airway Basal Stem Cell Homeostasis

Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Cody J. Aros, Manash K. Paul, Carla J. Pantoja, Bharti Bisht, Luisa K. Meneses, Preethi Vijayaraj, Jenna M. Sandlin, Bryan France, Jonathan A. Tse, Michelle W. Chen, David W. Shia, Tammy M. Rickabaugh, Robert Damoiseaux, Brigitte N. GompertsSummaryMechanisms underpinning airway epithelial homeostatic maintenance and ways to prevent its dysregulation remain elusive. Herein, we identify that β-catenin phosphorylated at Y489 (p-β-cateninY489) emerges during human squamous lung cancer progression. This led us to develop a model of airway basal stem cell (ABSC) hyperproliferation by driving Wnt/β-catenin signaling, resulting in a morphology that resembles premalignant lesions and loss of ciliated cell differentiation. To identify small molecules that could reverse this process, we performed a high-throughput drug screen for inhibitors of Wnt/β-catenin signaling. Our studies unveil Wnt inhibitor compound 1 (WIC1), which suppresses T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) activity, reduces ABSC proliferation, induces ciliated cell differentiation, and decreases nuclear p-β-cateninY489. Collectively, our work elucidates a dysregulated Wnt/p-β-cateninY489 axis in lung premalignancy that can be modeled in vitro and identifies a Wnt/β-catenin inhibitor that promotes airway homeostasis. WIC1 may therefore serve as a tool compound in regenerative med...
Source: Cell Reports - Category: Cytology Source Type: research

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Source: Environment International - Category: Environmental Health Authors: Tags: Environ Int Source Type: research
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Source: J Cell Mol Med - Category: Molecular Biology Authors: Tags: J Cell Mol Med Source Type: research
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Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
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Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
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Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
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Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
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Source: Medical Science Monitor - Category: Research Tags: Med Sci Monit Source Type: research
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Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Airway cell biology and immunopathology Source Type: research
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Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
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Source: J Cell Mol Med - Category: Molecular Biology Authors: Tags: J Cell Mol Med Source Type: research
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