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Mol Cancer Ther. 2019 Jun;18(6):1045-1056. doi: 10.1158/1535-7163.MCT-18-0146. Epub 2019 Apr 8.

Inhibition of Ubiquitin-Specific Protease 14 Suppresses Cell Proliferation and Synergizes with Chemotherapeutic Agents in Neuroblastoma.

Author information

1
Division of Pediatric Surgery, Texas Children's Hospital Department of Surgery, Michael E. DeBakey Department of Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
2
Department of Pediatrics, Texas Children's Cancer Center, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
3
Department of Pediatrics, Texas Children's Cancer Center, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. nuchtern@bcm.edu jianhuay@bcm.edu.
4
Division of Pediatric Surgery, Texas Children's Hospital Department of Surgery, Michael E. DeBakey Department of Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. nuchtern@bcm.edu jianhuay@bcm.edu.

Abstract

Neuroblastoma is the most common extracranial malignant solid tumor in children, and drug resistance is a major reason for poor outcomes. Elevated proteasome activity plays an important role in neuroblastoma tumor development and resistance to conventional chemotherapy. Ubiquitin-specific protease 14 (USP14), one of three deubiquitinases associated with the regulatory subunit of the proteasome, is emerging as a potential therapeutic target in multiple tumor types. However, the role of USP14 in neuroblastoma is yet to be elucidated. We found that USP14 inhibition in neuroblastoma via knockdown or a specific inhibitor such as b-AP15 suppressed cell proliferation by inducing cell apoptosis. Furthermore, b-AP15 significantly inhibited neuroblastoma tumor growth in NGP and SH-SY5Y xenograft mouse models. For combination treatment, b-AP15 plus conventional chemotherapeutic agents such as doxorubicin or VP-16 resulted in synergistic antitumor effects on neuroblastoma. Our study demonstrates that USP14 is required for cell viability and is a novel therapeutic target in neuroblastoma. Moreover, USP14 inhibition may add value in combination therapy due to its powerful synergistic effects in treating neuroblastoma.

PMID:
30962318
PMCID:
PMC6565366
[Available on 2020-06-01]
DOI:
10.1158/1535-7163.MCT-18-0146

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