Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma
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| Publicado en: | bioRxiv (Dec 20, 2024) |
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| Autor principal: | |
| Otros Autores: | , , , , , , , , , , , |
| Publicado: |
Cold Spring Harbor Laboratory Press
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| Materias: | |
| Acceso en línea: | Citation/Abstract Full text outside of ProQuest |
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| Resumen: | Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens on normal human fibroblasts by performing RNA sequencing. Our data uncovered changes in expression and regulation of Wnt signaling pathway members. Building on this observation, we bioinformatically evaluated various Wnt pathway perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its anti-tumor activity in other cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium targets multiple MCC vulnerabilities. Pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and non-canonical Wnt signaling but also inhibits cancer cell growth by activating p53-mediated apoptosis, disrupting mitochondrial function, and inducing endoplasmic reticulum stress. Finally, we demonstrated that pyrvinium reduces tumor growth in an MCC mouse xenograft model. These findings offer a new understanding of the role of Wnt signaling in MCC and highlight the utility of pyrvinium as a potential treatment for MCC.Competing Interest StatementThe authors have declared no competing interest.Footnotes* In this revised version, we added a third mouse xenograft study to show pyrvinium remains effective at lower doses, added siRNA and overexpression perturbations, coupled with use of the TopGFP TCF/LEF reporter system, to show precisely how Wnt signaling regulates neuroendocrine cell fate in MCC, and Validated our results in neonatal human dermal fibroblasts (nHDF), a type of skin cell in which Merkel cell polyomavirus has been shown to replicate; We have Figure 3 - 7 revised; Supplemental files updated; authors updated. |
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| ISSN: | 2692-8205 |
| DOI: | 10.1101/2023.11.01.565218 |
| Fuente: | Biological Science Database |