title: USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis.
abstract: Neuroblastoma (NB) is a common pediatric cancer and contributes to more than 15% of all pediatric cancer-related deaths. Unlike adult tumors, recurrent somatic mutations in NB, such as tumor protein 53 (p53) mutations, occur with relative paucity. In addition, p53 downstream function is intact in NB cells with wild-type p53, suggesting that reactivation of p53 may be a viable therapeutic strategy for NB treatment. Herein, we report that the ubiquitin-specific protease 7 (USP7) inhibitor, P22077, potently induces apoptosis in NB cells with an intact USP7-HDM2-p53 axis but not in NB cells with mutant p53 or without human homolog of MDM2 (HDM2) expression. In this study, we found that P22077 stabilized p53 by inducing HDM2 protein degradation in NB cells. P22077 also significantly augmented the cytotoxic effects of doxorubicin (Dox) and etoposide (VP-16) in NB cells with an intact USP7-HDM2-p53 axis. Moreover, P22077 was found to be able to sensitize chemoresistant LA-N-6 NB cells to chemotherapy. In an in vivo orthotopic NB mouse model, P22077 significantly inhibited the xenograft growth of three NB cell lines. Database analysis of NB patients shows that high expression of USP7 significantly predicts poor outcomes. Together, our data strongly suggest that targeting USP7 is a novel concept in the treatment of NB. USP7-specific inhibitors like P22077 may serve not only as a stand-alone therapy but also as an effective adjunct to current chemotherapeutic regimens for treating NB with an intact USP7-HDM2-p53 axis.
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Fan
authors.forename: J
authors.initials: J
authors.lastname: Cheng
authors.forename: S A
authors.initials: SA
authors.lastname: Vasudevan
authors.forename: J
authors.initials: J
authors.lastname: Dou
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: R H
authors.initials: RH
authors.lastname: Patel
authors.forename: I T
authors.initials: IT
authors.lastname: Ma
authors.forename: Y
authors.initials: Y
authors.lastname: Rojas
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: J M
authors.initials: JM
authors.lastname: Shohet
authors.forename: J G
authors.initials: JG
authors.lastname: Nuchtern
authors.forename: E S
authors.initials: ES
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017405:Herpes Simplex Virus Protein Vmw65 / Q000378:metabolism; D006801:Humans; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000076084:Ubiquitin-Specific Peptidase 7; D023041:Xenograft Model Antitumor Assays
chemical_list: C570895:1-(5-((2,4-difluorophenyl)thio)-4-nitrothiophen-2-yl)ethanone; D017405:Herpes Simplex Virus Protein Vmw65; D011480:Protease Inhibitors; D013876:Thiophenes; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7