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USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis
Fan, Y-H; Cheng, J.; Vasudevan, S. A.; Dou, J.; Zhang, H.; Patel, R. H.; Ma, I. T.; Rojas, Y.; Zhao, Y.; Yu, Y.; Zhang, H.; Shohet, J. M.; Nuchtern, J. G.; Kim, E. S.; Yang, J.
2013
Source PublicationCELL DEATH & DISEASE
ISSN2041-4889
Volume4Issue:10
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.

KeywordNeuroblastoma Usp7 Inhibitor P22077 P53 Chemotherapy
DOI10.1038/cddis.2013.400
Indexed BySCI
WOS IDWOS:000326967100053
Citation statistics
Cited Times:62[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.xjipc.cas.cn/handle/365002/3862
Collection省部共建新疆特有药用资源利用重点实验室
AffiliationBaylor Coll Med, Dan L Duncan Canc Ctr, Texas Childrens Canc Ctr, Dept Pediat, Houston, TX 77030 USA;Baylor Coll Med, Dan L Duncan Canc Ctr, Div Pediat Surg, Michael E DeBakey Dept Surg, Houston, TX 77030 USA;Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA;Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Xinjiang Key Lab Plant Resources & Nat Prod Chem, Urumqi 830011, Xinjiang, Peoples R China
Recommended Citation
GB/T 7714
Fan, Y-H,Cheng, J.,Vasudevan, S. A.,et al. USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis[J]. CELL DEATH & DISEASE,2013,4(10).
APA Fan, Y-H.,Cheng, J..,Vasudevan, S. A..,Dou, J..,Zhang, H..,...&Yang, J..(2013).USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis.CELL DEATH & DISEASE,4(10).
MLA Fan, Y-H,et al."USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis".CELL DEATH & DISEASE 4.10(2013).
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