VLX1570 suppresses neuroblastoma growth through inhibition of PCNA-associated proliferative signaling and potentiates cisplatin antitumor activity

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Despite intensive multimodal therapy, high-risk neuroblastoma remains associated with poor clinical outcomes because of treatment resistance, recurrence, and progressive disease, underscoring the need for new therapeutic strategies. We investigated whether proteasome-associated deubiquitinating enzymes are therapeutically relevant in neuroblastoma by assessing ubiquitin C-terminal hydrolase L5 (UCHL5) and ubiquitin-specific protease 14 (USP14) expression in neuroblastoma tissues and evaluating the antitumor activity of VLX1570 in preclinical models. Immunohistochemical (IHC) analysis showed stronger UCHL5 and USP14 immunoreactivity in neuroblastoma tissues than in normal peripheral nerve tissue. In human neuroblastoma cell lines IMR-32, SK-N-SH, and SH-SY5Y, VLX1570 reduced cell viability in a dose- and time-dependent manner, induced apoptosis, and triggered G2/M arrest. These effects were accompanied by induction of CCAAT/enhancer-binding protein homologous protein (CHOP) and suppression of proliferating cell nuclear antigen (PCNA)-associated proliferative signaling, as reflected by reduced expression of PCNA, phospho-histone H3, and Bcl-2 together with increased p21 and p53 expression. PCNA knockdown experiments further supported inhibition of PCNA-associated proliferative signaling as a functionally relevant component of VLX1570-induced cytotoxicity. In addition, VLX1570 enhanced cisplatin-induced apoptosis in vitro and potentiated cisplatin antitumor activity in neuroblastoma xenograft models. Together, these findings support proteasome-associated deubiquitinating enzyme inhibition as a pharmacologic strategy in neuroblastoma and provide a rationale for further evaluation of VLX1570, particularly in combination with cisplatin.

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