Narciclasine is a novel YAP inhibitor that disturbs interaction between YAP and TEAD4
Rie Kawamoto1, Naoko Nakano1, Haruka Ishikawa1
1Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
Abstract:
Yes-associated protein (YAP) is involved in development, cell growth, cell size, and homeostasis and plays a key role in the progression of various cancers. Among them, constitutive activation of YAP can often be observed in malignant mesothelioma, which arises in the pleura, peritoneum, and pericardium because of inactivation of the Hippo pathway. To date, however, only less-effective treatments such as chemotherapy, radiation therapy, and surgery are available for patients with malignant mesothelioma. In this study, we identified narciclasine as a novel YAP inhibitor that prevents YAP from interacting with TEAD4 because it competes with TEAD4 for binding to YAP. Furthermore, narciclasine could perturb the cell growth and colony formation of malignant mesothelioma NCI-H290 cells in addition to inhibiting their growth in nude mice. Therefore, narciclasine might be a potential seed for a novel antitumor drug against malignant mesothelioma and other cancers in which hyperactivation and/or overexpression of YAP are observed.
Insights
Narciclasine inhibits Yes-associated protein (YAP) by blocking its interaction with TEAD4. This novel YAP inhibitor shows potential as an antitumor drug for malignant mesothelioma and other cancers driven by YAP.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Yes-associated protein (YAP) is crucial for cell growth and homeostasis, and its aberrant activation drives various cancers, notably malignant mesothelioma.
- Current treatments for malignant mesothelioma, including chemotherapy, radiation, and surgery, offer limited efficacy.
- Inactivation of the Hippo pathway frequently leads to constitutive YAP activation in malignant mesothelioma.
Purpose of the Study:
- To identify novel inhibitors of YAP.
- To investigate the therapeutic potential of narciclasine against malignant mesothelioma.
- To elucidate the mechanism by which narciclasine inhibits YAP activity.
Main Methods:
- Identification of narciclasine as a YAP inhibitor.
- Assessment of narciclasine's effect on YAP-TEAD4 interaction.
- Evaluation of narciclasine's impact on malignant mesothelioma cell growth, colony formation, and tumor growth in nude mice.
Main Results:
- Narciclasine was identified as a novel inhibitor of YAP, preventing its interaction with TEAD4 by competing for binding.
- Narciclasine significantly inhibited the proliferation and colony formation of malignant mesothelioma NCI-H290 cells.
- Narciclasine demonstrated antitumor activity by inhibiting the growth of malignant mesothelioma in vivo.
Conclusions:
- Narciclasine acts as a YAP inhibitor by disrupting the YAP-TEAD4 complex.
- Narciclasine exhibits potent anti-cancer effects against malignant mesothelioma cells and tumors.
- Narciclasine represents a promising candidate for developing new anti-cancer therapeutics targeting YAP hyperactivation.
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