Verteporfin induces apoptosis and reduces the stem cell-like properties in Neuroblastoma tumour-initiating cells through inhibition of the YAP/TAZ pathway

• DOI: 10.1016/j.ejphar.2020.173829
• Publication Date: 2020-12-18T14:50:11Z
• Authors: Pina Fusco; Elena Mattiuzzo; Chiara Frasson; Giampietro Viola; Elisa Cimetta; Maria Rosaria Esp...; Gian Paolo Tonini
• Keywords: 0303 health sciences; Drug Repositioning; Verteporfin; Apoptosis; YAP-Signaling Proteins; 3. Good health; Neuroblastoma; 03 medical and health sciences; Cell Movement; Cell Line, Tumor; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Antineoplastic Combined Chemotherapy Protocols; Neoplastic Stem Cells; Trans-Activators; Humans; Neoplasm Invasiveness; Cisplatin; Neuroblastoma; Tumour initiating cells (TICs); Verteporfin (VP); YAP/TAZ; Side-Population Cells; Adaptor Proteins, Signal Transducing; Cell Proliferation; Etoposide; Signal Transduction; Transcription Factors

Neuroblastoma is an embryonal malignancy of early childhood arising from the embryonic sympatho-adrenal lineage of the neural crest. About half of all cases are currently classified as high-risk of disease recurrence, with an overall survival rate of less than 40% at 5 years despite intensive therapy. Recent studies on matched primary tumours and at the relapse revealed downregulation of genes transcriptionally silenced by YAP as significant association with neuroblastoma relapse. Here, we evaluated the pharmacological targeting of YAP/TAZ with the YAP/TAZ-TEAD inhibitor Verteporfin (VP) in Tumour Initiating Cells (TICs) derived from High-Risk Neuroblastoma patients. VP treatment suppresses YAP/TAZ expression, induces apoptosis and causes the re-organization of the cytoskeleton reducing cells migration and clonogenic ability. Moreover, VP reduces the percentage of side population cells and ABC transporters involved in drug resistance, and the percentage of stem cell subpopulations CD133+ and CD44+ of TICs. Finally, we demonstrated that VP sensitizes TICs to the standard drugs used for neuroblastoma therapy etoposide and cis-platin opening the way to use VP as drug repositioning candidate for recurrent neuroblastoma.