Sanna, Luca (2018) Antiproliferative activity of Verteporfin in Embryonal and Alveolar Rhabdomyosarcoma cell lines. Doctoral Thesis.
Rhabdomyosarcoma (RMS) is a pediatric tumor, which arises from muscle precursor cells. Recently, it has been demonstrated that Hippo Pathway (Hpo) is involved in tumorigenesis of RMS. Thanks to its kinase cascade, which activates Yes-Associated Protein 1 (YAP1-YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), Hpo is able to activate several physiological and biological features. YAP and TAZ are the heart of Hpo and they showed to have both cytoplasmic and nuclear role. In the nucleus, YAP is able to bind TEAD factors and constitute a complex that activates the transcription of several genes such as MYC, Tbx5 and PAX8 or maintains the stability of others like p73. The key role of YAP and TAZ in cancer is leading to the development of new compounds able to block their action. One of these drugs is called Verteporfin (VP). This molecule is able to stop the formation of YAP/TEAD complex in the nucleus. Considering that RMS is an aggressive tumor and that YAP recovers an important role on it, the aim of this project was to understand if VP is able to have a specific effect on RMS cell lines. This work showed that VP has an antiproliferative action on RMS cell lines. VP perturbs cell cycle in a different manner depending on RMS cell lines. Through its action, VP modifies also the phenotype of RMS cells. Moreover, this drug is able to induce the activation of apoptosis mechanism through the cleavage of PARP protein in RMS cell lines. Furthermore, siRNA-induced knock down of YAP clarifies that VP induces anti proliferative action through other mechanism.
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