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题名: USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis
作者: 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.
关键词: neuroblastoma ; USP7 inhibitor ; P22077 ; p53 ; chemotherapy
刊名: CELL DEATH & DISEASE
发表日期: 2013
DOI: 10.1038/cddis.2013.400
卷: 4, 期:10
收录类别: SCI
资助者: NIH-NINDS
摘要: 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.
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内容类型: 期刊论文
URI标识: http://ir.xjipc.cas.cn/handle/365002/3862
Appears in Collections:新疆维吾尔自治区植物资源化学重点实验室 _期刊论文

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作者单位: Baylor 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:
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).
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