A small-molecule inhibitor of UBE2N induces neuroblastoma cell death via activation of p53 and JNK pathways
Cheng, J.; Fan, Y-H; Xu, X.; Zhang, H.; Dou, J.; Tang, Y.; Zhong, X.; Rojas, Y.; Yu, Y.; Zhao, Y.; Vasudevan, S. A.; Zhang, H.; Nuchtern, J. G.; Kim, E. S.; Chen, X.; Lu, F.; Yang, J.
2014
发表期刊CELL DEATH & DISEASE
ISSN2041-4889
卷号5期号:2
摘要

Neuroblastoma (NB) is the most common extracranial neoplasm in children. In NB, loss of p53 function is largely due to cytoplasmic sequestration rather than mutation. Ubiquitin-conjugating enzyme E2 N (UBE2N), also known as Ubc13, is an E2 ubiquitin-conjugating enzyme that promotes formation of monomeric p53 that results in its cytoplasmic translocation and subsequent loss of function. Therefore, inhibition of UBE2N may reactivate p53 by promoting its nuclear accumulation. Here, we show that NSC697923, a novel UBE2N inhibitor, exhibits potent cytotoxicity in a panel of NB cell lines evidenced by its ability to induce apoptosis. In p53 wild-type NB cells, NSC697923 induced nuclear accumulation of p53, which led to its increased transcriptional activity and tumor suppressor function. Interestingly, in p53 mutant NB cells, NSC697923 induced cell death by activating JNK pathway. This effect was reversible by blocking JNK activity with its selective inhibitor, SP600125. More importantly, NSC697923 impeded cell growth of chemoresistant LA-N-6 NB cell line in a manner greater than conventional chemotherapy drugs doxorubicin and etoposide. NSC697923 also revealed in vivo antitumor efficacy in NB orthotopic xenografts. Taken together, our results suggest that UBE2N is a potential therapeutic target in NB and provide a basis for the rational use of UBE2N inhibitors like NSC697923 as a novel treatment option for NB patients.

DOI10.1038/cddis.2014.54
收录类别SCI
WOS记录号WOS:000332223700036
引用统计
被引频次:32[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.xjipc.cas.cn/handle/365002/3805
专题省部共建新疆特有药用资源利用重点实验室
作者单位Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Microbiol, Beijing 100191, Peoples R China;Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Ctr Infect Dis, Beijing 100191, Peoples R China; Baylor Coll Med, Texas Childrens Canc Ctr, Dept Pediat, Dan L Duncan Canc Ctr, 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; Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Hematol, Wuhan 430030, Hubei, Peoples R China;Harbin Med Univ, Affiliated Hosp 2, Dept Gen Surg, Harbin 150086, Heilongjiang, Peoples R China;Baylor Coll Med, Div Pediat Surg, Michael E DeBakey Dept Surg, Dan L Duncan Canc Ctr, Houston, TX 77030 USA
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Cheng, J.,Fan, Y-H,Xu, X.,et al. A small-molecule inhibitor of UBE2N induces neuroblastoma cell death via activation of p53 and JNK pathways[J]. CELL DEATH & DISEASE,2014,5(2).
APA Cheng, J..,Fan, Y-H.,Xu, X..,Zhang, H..,Dou, J..,...&Yang, J..(2014).A small-molecule inhibitor of UBE2N induces neuroblastoma cell death via activation of p53 and JNK pathways.CELL DEATH & DISEASE,5(2).
MLA Cheng, J.,et al."A small-molecule inhibitor of UBE2N induces neuroblastoma cell death via activation of p53 and JNK pathways".CELL DEATH & DISEASE 5.2(2014).
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