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Published on: May 12, 2017
High-Throughput Drug Screening Identifies a Potent Wnt Inhibitor that Promotes Airway Basal Stem Cell Homeostasis.
Cody J Aros1, Manash K Paul2, Carla J Pantoja3
1UCLA Department of Molecular Biology Interdepartmental Program, UCLA, Los Angeles, CA 90095, USA; UCLA Medical Scientist Training Program, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
Researchers identified a key protein, phosphorylated beta-catenin (p-β-catenin), involved in lung cancer. They found a compound (WIC1) that reverses abnormal cell growth and promotes airway repair, offering potential for regenerative medicine.
Area of Science:
- Pulmonary Medicine
- Molecular Biology
- Cancer Research
Background:
- Airway epithelial homeostasis is crucial for lung function, but mechanisms of its maintenance and dysregulation are not fully understood.
- Aberrant Wnt/β-catenin signaling is implicated in various cancers, including lung cancer, but its specific role in airway premalignancy requires further elucidation.
Purpose of the Study:
- To investigate the role of phosphorylated β-catenin (p-β-catenin) in lung cancer progression and airway epithelial stem cell (ABSC) behavior.
- To identify small molecules capable of inhibiting Wnt/β-catenin signaling and restoring airway homeostasis.
Main Methods:
- Developed an in vitro model of airway basal stem cell (ABSC) hyperproliferation by activating Wnt/β-catenin signaling.
- Conducted a high-throughput drug screen to identify inhibitors of Wnt/β-catenin signaling.
- Evaluated the efficacy of identified compounds in suppressing T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) activity, reducing ABSC proliferation, and promoting ciliated cell differentiation.
Main Results:
- Identified phosphorylated β-catenin at Y489 (p-β-cateninY489) as a marker associated with human squamous lung cancer progression.
- The Wnt/β-catenin signaling activation led to ABSC hyperproliferation and loss of ciliated cell differentiation, mimicking premalignant lesions.
- Discovered Wnt inhibitor compound 1 (WIC1), which effectively suppresses TCF/LEF activity, reduces ABSC proliferation, restores ciliated cell differentiation, and decreases nuclear p-β-cateninY489.
Conclusions:
- A dysregulated Wnt/p-β-cateninY489 axis plays a significant role in lung premalignancy.
- WIC1 is a potent Wnt/β-catenin inhibitor that can restore airway homeostasis in vitro.
- WIC1 holds promise as a tool compound for regenerative medicine strategies aimed at repairing airway injury.
