Targeting the SPC25/RIOK1/MYH9 Axis to Overcome Tumor Stemness and Platinum Resistance in Epithelial Ovarian Cancer.

IF 3.784 3区化学 Q1 Chemistry ACS Combinatorial Science Pub Date : 2024-11-03 DOI:10.1002/advs.202406688

Xingyu Jiang, Muwen Yang, Weijing Zhang, Dongni Shi, Yue Li, Lixin He, Shumei Huang, Boyu Chen, Xuwei Chen, Lingzhi Kong, Yibing Pan, Pinwei Deng, Rui Wang, Ying Ouyang, Xiangfu Chen, Jun Li, Zheng Li, Hequn Zou, Yanna Zhang, Libing Song

{"title":"Targeting the SPC25/RIOK1/MYH9 Axis to Overcome Tumor Stemness and Platinum Resistance in Epithelial Ovarian Cancer.","authors":"Xingyu Jiang, Muwen Yang, Weijing Zhang, Dongni Shi, Yue Li, Lixin He, Shumei Huang, Boyu Chen, Xuwei Chen, Lingzhi Kong, Yibing Pan, Pinwei Deng, Rui Wang, Ying Ouyang, Xiangfu Chen, Jun Li, Zheng Li, Hequn Zou, Yanna Zhang, Libing Song","doi":"10.1002/advs.202406688","DOIUrl":null,"url":null,"abstract":"<p><p>In epithelial ovarian cancer (EOC), platinum resistance, potentially mediated by cancer stem cells (CSCs), often leads to relapse and treatment failure. Here, the role of spindle pole body component 25 (SPC25) as a key determinant promoting stemness and platinum resistance in EOC cells, with its expression being correlated with adverse clinical outcomes is delineated. Mechanistically, SPC25 acts as a scaffolding platform, orchestrating the assembly of an SPC25/RIOK1/MYH9 trimeric complex, triggering RIOK1-mediated phosphorylation of MYH9 at Ser1943. This prompts MYH9 to disengage from the cytoskeleton, augmenting its nuclear accumulation, thus potentiating CTNNB1 transcription and subsequent activation of Wnt/β-catenin signaling. CBP1, a competitive inhibitory peptide, can disrupt the formation of the aforementioned trimeric complex, diminishing the activity of the SPC25/RIOK1/MYH9 axis-mediated Wnt/β-catenin signaling, and thus attenuate CSC phenotypes, thereby enhancing platinum efficacy in vitro, in vivo, and in patient-derived organoids. Therefore, targeting the SPC25/RIOK1/MYH9 axis, which mediates the maintenance of stemness and platinum resistance in EOC cells, may enhance platinum sensitivity and increase survival in patients with EOC.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.7840,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Combinatorial Science","FirstCategoryId":"88","ListUrlMain":"https://doi.org/10.1002/advs.202406688","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Chemistry","Score":null,"Total":0}

引用次数: 0

Abstract

In epithelial ovarian cancer (EOC), platinum resistance, potentially mediated by cancer stem cells (CSCs), often leads to relapse and treatment failure. Here, the role of spindle pole body component 25 (SPC25) as a key determinant promoting stemness and platinum resistance in EOC cells, with its expression being correlated with adverse clinical outcomes is delineated. Mechanistically, SPC25 acts as a scaffolding platform, orchestrating the assembly of an SPC25/RIOK1/MYH9 trimeric complex, triggering RIOK1-mediated phosphorylation of MYH9 at Ser1943. This prompts MYH9 to disengage from the cytoskeleton, augmenting its nuclear accumulation, thus potentiating CTNNB1 transcription and subsequent activation of Wnt/β-catenin signaling. CBP1, a competitive inhibitory peptide, can disrupt the formation of the aforementioned trimeric complex, diminishing the activity of the SPC25/RIOK1/MYH9 axis-mediated Wnt/β-catenin signaling, and thus attenuate CSC phenotypes, thereby enhancing platinum efficacy in vitro, in vivo, and in patient-derived organoids. Therefore, targeting the SPC25/RIOK1/MYH9 axis, which mediates the maintenance of stemness and platinum resistance in EOC cells, may enhance platinum sensitivity and increase survival in patients with EOC.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

靶向 SPC25/RIOK1/MYH9 轴克服上皮性卵巢癌的肿瘤干性和铂类抗药性

在上皮性卵巢癌（EOC）中，可能由癌症干细胞（CSC）介导的铂类抗药性常常导致复发和治疗失败。本文阐述了纺锤极体成分25（SPC25）的作用，它是促进EOC细胞干性和铂金耐药性的关键决定因素，其表达与不良临床结果相关。从机理上讲，SPC25作为一个支架平台，协调SPC25/RIOK1/MYH9三聚体复合物的组装，触发RIOK1介导的MYH9在Ser1943处的磷酸化。这促使 MYH9 脱离细胞骨架，增加其核积累，从而促进 CTNNB1 的转录和随后 Wnt/β-catenin 信号的激活。CBP1是一种竞争性抑制肽，它能破坏上述三聚体复合物的形成，降低SPC25/RIOK1/MYH9轴介导的Wnt/β-catenin信号的活性，从而减轻CSC表型，提高铂在体外、体内和患者衍生器官组织中的疗效。因此，靶向SPC25/RIOK1/MYH9轴（该轴介导EOC细胞的干性和铂抗性的维持）可能会增强EOC患者对铂的敏感性并提高存活率。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

ACS Combinatorial Science CHEMISTRY, APPLIED-CHEMISTRY, MEDICINAL

自引率

0.00%

发文量

审稿时长

1 months

期刊介绍： The Journal of Combinatorial Chemistry has been relaunched as ACS Combinatorial Science under the leadership of new Editor-in-Chief M.G. Finn of The Scripps Research Institute. The journal features an expanded scope and will build upon the legacy of the Journal of Combinatorial Chemistry, a highly cited leader in the field.