USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis

Y-H Fan,I T Ma,S A Vasudevan,Y Yu,J Yang,J G Nuchtern,R H Patel,H Zhang,Y Zhao,J Dou,J Cheng,Y Rojas,E S Kim,J M Shohet

doi:10.1038/cddis.2013.400

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.

Highlights

It is the most common extracranial solid tumor in children and accounts for more than 15% of all pediatric cancer-related deaths.[1,2] Despite dramatic escalations in therapy over the past years, only modest improvements in overall survival of high-risk NB patients have been achieved.[3,4,5,6] novel therapeutic targets and strategies are urgently needed to significantly improve the therapeutic efficacy
Our results demonstrate that P22077 potently induces cell death in a subset of NB cell lines
Our results demonstrate that P22077 enhances the cytotoxic effect of Dox and VP-16, and this effect is dependent on an intact ubiquitin-specific protease 7 (USP7)-HDM2-P53 axis but independent of MYCN status in NB cells

Summary

Introduction

It is the most common extracranial solid tumor in children and accounts for more than 15% of all pediatric cancer-related deaths.[1,2] Despite dramatic escalations in therapy over the past years, only modest improvements in overall survival of high-risk NB patients have been achieved.[3,4,5,6] novel therapeutic targets and strategies are urgently needed to significantly improve the therapeutic efficacy. Recurrent somatic mutations in NB occur with relative paucity.[7] It suggests that reactivation of critical tumor suppressor genes, such as tumor protein 53 (p53), may be a viable strategy to treat NB. The tumor suppressor p53 is one of the most studied and most important regulators of multiple signaling pathways, including normal cellular processes and those triggered by diverse cellular stresses.[8,9,10] p53 induces cell growth arrest, apoptosis, and senescence and is mutated in over 50% of all cancers.[11,12] In NB, p53 mutations are exceedingly rare and occur in less than 2% of primary tumors.[7,13,14]. USP7 deficiency in mouse embryonic fibroblasts (MEFs) greatly reduces the half-life of MDM2 and activates p53.26 Taken together, these studies suggest that

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