ONC201在神经母细胞瘤亚群中发挥的致癌作用超出了其线粒体干扰作用。

IF 4.8 3区 医学 Q1 GENETICS & HEREDITY
Journal of Molecular Medicine-Jmm Pub Date : 2025-05-01 Epub Date: 2025-04-10 DOI:10.1007/s00109-025-02541-0
Jyun-Hong Jiang, Yu-Han Lin, Pei-Lin Liao, Ting-Ya Chen, Hui-Ching Chuang, Chao-Cheng Huang, Wen-Ming Hsu, Jiin-Haur Chuang, Wei-Shiung Lian
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引用次数: 0

摘要

神经母细胞瘤(NB)是儿科肿瘤学中一项艰巨的挑战,由于其复杂的分子景观,需要多方面的治疗方法。ONC201是一种具有抗线粒体蛋白酶ClpP和ClpX的有效抗癌特性的吡普利酮抗生素化合物,是一种有前景的候选药物。尽管显示出早期的临床前景,特别是在mycn扩增的NB中,但其在非mycn扩增的NB中的疗效仍然是一个值得研究的课题。在这项研究中,我们扩大了ONC201的覆盖范围,以治疗非mycn扩增的NB,我们的数据表明ONC201无法降低含有SK-N-AS或SK-N-FI细胞系的动物模型中的肿瘤生长。有趣的是,ONC201诱导致癌标志物c-Myc和LGR5的表达,同时下调肿瘤抑制因子ATRX。虽然它不能减弱非mycn扩增NB异种移植物的肿瘤新生血管,但其效果与mycn扩增NB异种移植物不同。经ONC201处理的Rho 0 (ρ0)-SK-N-AS细胞在亲代SK-N-AS细胞中表现出类似的观察趋势,包括LGR5上调和ATRX下调,这表明ONC201的多方面作用超出了线粒体目标。我们的阐明强调了在使用ONC201单药治疗缺乏mycn扩增的NB时需要识别分子特征。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ONC201 exerts oncogenic effects beyond its mitochondria-disturbing role in neuroblastoma subsets.

Neuroblastoma (NB) is a formidable challenge in pediatric oncology due to its intricate molecular landscape, necessitating multifaceted therapeutic approaches. ONC201 is an imipridone antibiotic compound with a promising drug candidate leveraging its potent anticancer properties against the mitochondrial proteases ClpP and ClpX. Despite demonstrating early clinical promise, particularly in MYCN-amplified NB, its efficacy in non-MYCN-amplified NB remains a subject worthy of investigation. In this study, we extended the coverage of ONC201 to treat non-MYCN-amplified NB, and our data implicated ONC201's inability to reduce tumor growth in animal models harboring SK-N-AS or SK-N-FI cell lines. Interestingly, ONC201 induced the expression of oncogenic markers c-Myc and LGR5 while downregulating the tumor suppressor ATRX. While it fails to attenuate tumor neovascularization in non-MYCN-amplified NB xenografts, its effectiveness differs from that of its MYCN-amplified counterpart. Rho zero (ρ0)-SK-N-AS cells treated with ONC201 showed comparable observed trends in parental SK-N-AS cells, including LGR5 upregulation and ATRX downregulation, suggesting that ONC201's multifaceted actions extend beyond mitochondrial targets. Our elucidation highlights the need to discern molecular signatures when deploying ONC201 monotherapy against NB, which lacks MYCN-amplification.

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来源期刊
Journal of Molecular Medicine-Jmm
Journal of Molecular Medicine-Jmm 医学-医学:研究与实验
CiteScore
9.30
自引率
0.00%
发文量
100
审稿时长
1.3 months
期刊介绍: The Journal of Molecular Medicine publishes original research articles and review articles that range from basic findings in mechanisms of disease pathogenesis to therapy. The focus includes all human diseases, including but not limited to: Aging, angiogenesis, autoimmune diseases as well as other inflammatory diseases, cancer, cardiovascular diseases, development and differentiation, endocrinology, gastrointestinal diseases and hepatology, genetics and epigenetics, hematology, hypoxia research, immunology, infectious diseases, metabolic disorders, neuroscience of diseases, -omics based disease research, regenerative medicine, and stem cell research. Studies solely based on cell lines will not be considered. Studies that are based on model organisms will be considered as long as they are directly relevant to human disease.
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