title: A small-molecule inhibitor of UBE2N induces neuroblastoma cell death via activation of p53 and JNK pathways.
abstract: 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.
authors.affiliation: 1] Department of Microbiology & Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, Beijing 100191, China [2] Department of Pediatrics, Texas Children's Cancer Center, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Fan
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 1] Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [2] Xinjiang Key Laboratory of Plant Resources and Natural Products Chemistry, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, Xinjiang 830011, China.
authors.forename: J
authors.initials: J
authors.lastname: Dou
authors.affiliation: 1] Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [2] Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Tang
authors.affiliation: 1] Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [2] Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Rojas
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Vasudevan
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Nuchtern
authors.affiliation: Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Department of Microbiology & Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, Beijing 100191, China.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Microbiology & Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, Beijing 100191, China.
authors.forename: F
authors.initials: F
authors.lastname: Lu
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009447:Neuroblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C471607:UBE2N protein, human; D044763:Ubiquitin-Conjugating Enzymes; D048031:JNK Mitogen-Activated Protein Kinases