A small-molecule inhibitor of UBE2N induces neuroblastoma cell death via activation of p53 and JNK pathways.
A small-molecule inhibitor of UBE2N induces neuroblastoma cell death via activation of p53 and JNK pathways.
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UBE2N的小分子抑制剂通过激活p53和JNK途径诱导神经母细胞瘤死亡。
DOI：
10.1038/cddis.2014.54
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发表时间：
2014-02-20
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
神经母细胞瘤（NB）是儿童最常见的颅外肿瘤。在NB中，p53功能的丧失主要是由于细胞质隔离而不是突变。泛素偶联酶E2N (UBE2N)，也称为Ubc13，是一种E2泛素偶联酶，促进单体p53的形成，导致其细胞质易位和随后的功能丧失。因此，抑制UBE2N可能通过促进其核积累来重新激活p53。在这里，我们发现一种新的UBE2N抑制剂NSC697923在一组NB细胞系中表现出强大的细胞毒性，其诱导细胞凋亡的能力证明了这一点。在p53野生型NB细胞中，NSC697923诱导p53的核积累，导致其转录活性和抑瘤功能增加。有趣的是，在p53突变的NB细胞中，NSC697923通过激活JNK通路诱导细胞死亡。这种效应可以通过JNK的选择性抑制剂SP600125阻断其活性而逆转。更重要的是，NSC697923对LA-N-6 NB耐药细胞株的抑制作用大于常规化疗药物阿霉素和依托泊苷。NSC697923还显示了NB原位异种移植物的体内抗肿瘤作用。综上所述，我们的研究结果表明UBE2N是NB的潜在治疗靶点，为合理使用UBE2N抑制剂如NSC697923作为NB患者的新治疗选择提供了基础。
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.
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DOI：
10.1073/pnas.92.10.4407
发表时间：
1995-05-09
影响因子：
11.1
作者：
MOLL, UM;LAQUAGLIA, M;RIOU, G
通讯作者：
RIOU, G
影响因子：
8
作者：
Bykov, VJN;Zache, N;Wiman, KG
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影响因子：
4.8
作者：
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DOI：
10.1073/pnas.0700548104
发表时间：
2007-04-10
影响因子：
11.1
作者：
Fukushima, Toru;Matsuzawa, Shu-ichi;Reed, John C.
通讯作者：
Reed, John C.
影响因子：
7.2
作者：
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通讯作者：
Yang, Jianhua