The YAP1 Signaling Inhibitors, Verteporfin and CA3, Suppress the Mesothelioma Cancer Stem Cell Phenotype
| Autor: | H. Richard Alexander, McKayla B. Mickle, Sivaveera Kandasamy, Gautam Adhikary, Joseph S. Friedberg, Ellen A. Rorke, Richard L. Eckert |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Mesothelioma Cancer Research Cell Transfection Article 03 medical and health sciences Mice 0302 clinical medicine Cancer stem cell Medicine Animals Humans Molecular Biology Adaptor Proteins Signal Transducing YAP1 Photosensitizing Agents business.industry Verteporfin YAP-Signaling Proteins medicine.disease 030104 developmental biology medicine.anatomical_structure Phenotype Oncology Apoptosis 030220 oncology & carcinogenesis Cancer research Neoplastic Stem Cells Signal transduction business medicine.drug Signal Transduction Transcription Factors |
| Zdroj: | Mol Cancer Res |
| ISSN: | 1557-3125 |
| Popis: | Mesothelioma is an aggressive cancer that has a poor prognosis. Tumors develop in the mesothelial lining of the pleural and peritoneal cavities in response to asbestos exposure. Surgical debulking followed by chemotherapy is initially effective, but this treatment ultimately selects for resistant cells that form aggressive and therapy-resistant recurrent tumors. Mesothelioma cancer stem cells (MCS) are a highly aggressive subpopulation present in these tumors that are responsible for tumor maintenance and drug resistance. In this article, we examine the impact of targeting YAP1/TAZ/TEAD signaling in MCS cells. YAP1, TAZ, and TEADs are transcriptional mediators of the Hippo signaling cascade that activate gene expression to drive tumor formation. We show that two YAP1 signaling inhibitors, verteporfin and CA3, attenuate the MCS cell phenotype. Verteporfin or CA3 treatment reduces YAP1/TEAD level/activity to suppress MCS cell spheroid formation, Matrigel invasion, migration, and tumor formation. These agents also increase MCS cell apoptosis. Moreover, constitutively active YAP1 expression antagonizes inhibitor action, suggesting that loss of YAP1/TAZ/TEAD signaling is required for response to verteporfin and CA3. These agents are active against mesothelioma cells derived from peritoneal (epithelioid) and patient-derived pleural (sarcomatoid) mesothelioma, suggesting that targeting YAP1/TEAD signaling may be a useful treatment strategy. Implications: These studies suggest that inhibition of YAP1 signaling may be a viable approach to treating mesothelioma. |
| Databáze: | OpenAIRE |
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