RCN2 facilitates esophageal squamous cellular carcinoma metastasis and cisplatin resistance through UBR5-mediated PPP2CA ubiquitination and degradation

IF 22 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates Pub Date : 2026-03-01 Epub Date: 2025-12-04 DOI:10.1016/j.drup.2025.101339

Mengyuan Wu , Xu Huang , Miao Lin , Zhiyun Duan , Zitao Jian , Runze You , Peiyi Xie , Zhiwei Wu , Siyun Lin , Shaoyuan Zhang , Wenyi Xu , Heng Jiao , Han Tang , Lei Guo , Hao Wang , Weigang Guo , Lijie Tan

{"title":"RCN2 facilitates esophageal squamous cellular carcinoma metastasis and cisplatin resistance through UBR5-mediated PPP2CA ubiquitination and degradation","authors":"Mengyuan Wu , Xu Huang , Miao Lin , Zhiyun Duan , Zitao Jian , Runze You , Peiyi Xie , Zhiwei Wu , Siyun Lin , Shaoyuan Zhang , Wenyi Xu , Heng Jiao , Han Tang , Lei Guo , Hao Wang , Weigang Guo , Lijie Tan","doi":"10.1016/j.drup.2025.101339","DOIUrl":null,"url":null,"abstract":"<div><h3>Aims</h3><div>Metastatic progression and treatment resistance determine poor prognostic outcomes of patients with esophageal squamous cellular carcinoma (ESCC), highlighting the urgent need to understand the molecular mechanisms behind this. Reticulocalbin 2 (RCN2) is a calcium-binding protein localized in the endoplasmic reticulum lumen, which mediates tumor progression in various cancer types. However, the role of RCN2 in ESCC remains unexplored.</div></div><div><h3>Methods</h3><div>The influence of RCN2 on ESCC progression, metastasis, and cisplatin (CDDP) resistance was assessed both <em>in vitro</em> and <em>in vivo</em>. The downstream regulatory mechanism associated with RCN2 was screened through RNA-seq, TMT 10X mass spectrometry analysis, and LC-MS/MS analysis, which was further validated through Western blot, immunoprecipitation, immunofluorescence, GST pull-down assay, and rescue experiments.</div></div><div><h3>Results</h3><div>We observed high RCN2 expression in ESCC tumor tissues from patients with metastasis, which is correlated with a higher risk of metastasis and worse survival. PPP2CA, a catalytic subunit of protein phosphatase 2 A (PP2A), and ubiquitin protein ligase E3 component N-recognin 5 (UBR5) are determined as novel RCN2 functioning interactors. Mechanistically, RCN2 facilitates PPP2CA ubiquitination and degradation dependent on the HECT domain of UBR5, thereby activating the PI3K-AKT signaling pathway. Furthermore, the activated RCN2-PPP2CA-PI3K-AKT axis is validated in clinical specimens of ESCC. Finally, targeted suppression of RCN2 synergized with CDDP treatment to prevent tumor growth and metastasis in subcutaneous and lung metastasis models.</div></div><div><h3>Conclusions</h3><div>Overall, these findings identify RCN2 as a novel driver of ESCC metastasis and CDDP resistance. RCN2 could be a promising treatment target for ESCC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101339"},"PeriodicalIF":22.0000,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Resistance Updates","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1368764625001426","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/12/4 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}

引用次数: 0

Abstract

Aims

Metastatic progression and treatment resistance determine poor prognostic outcomes of patients with esophageal squamous cellular carcinoma (ESCC), highlighting the urgent need to understand the molecular mechanisms behind this. Reticulocalbin 2 (RCN2) is a calcium-binding protein localized in the endoplasmic reticulum lumen, which mediates tumor progression in various cancer types. However, the role of RCN2 in ESCC remains unexplored.

Methods

The influence of RCN2 on ESCC progression, metastasis, and cisplatin (CDDP) resistance was assessed both in vitro and in vivo. The downstream regulatory mechanism associated with RCN2 was screened through RNA-seq, TMT 10X mass spectrometry analysis, and LC-MS/MS analysis, which was further validated through Western blot, immunoprecipitation, immunofluorescence, GST pull-down assay, and rescue experiments.

Results

We observed high RCN2 expression in ESCC tumor tissues from patients with metastasis, which is correlated with a higher risk of metastasis and worse survival. PPP2CA, a catalytic subunit of protein phosphatase 2 A (PP2A), and ubiquitin protein ligase E3 component N-recognin 5 (UBR5) are determined as novel RCN2 functioning interactors. Mechanistically, RCN2 facilitates PPP2CA ubiquitination and degradation dependent on the HECT domain of UBR5, thereby activating the PI3K-AKT signaling pathway. Furthermore, the activated RCN2-PPP2CA-PI3K-AKT axis is validated in clinical specimens of ESCC. Finally, targeted suppression of RCN2 synergized with CDDP treatment to prevent tumor growth and metastasis in subcutaneous and lung metastasis models.

Conclusions

Overall, these findings identify RCN2 as a novel driver of ESCC metastasis and CDDP resistance. RCN2 could be a promising treatment target for ESCC.

查看原文本刊更多论文

RCN2通过ubr5介导的PPP2CA泛素化和降解促进食管鳞癌转移和顺铂耐药

转移进展和治疗耐药性决定了食管鳞状细胞癌（ESCC）患者预后不良的结果，强调了迫切需要了解其背后的分子机制。网状定位蛋白2 （Reticulocalbin 2, RCN2）是一种定位于内质网管腔的钙结合蛋白，在多种癌症类型中介导肿瘤进展。然而，RCN2在ESCC中的作用仍未被探索。方法体外和体内观察RCN2对ESCC进展、转移及顺铂耐药的影响。通过RNA-seq、TMT 10X质谱分析、LC-MS/MS分析筛选与RCN2相关的下游调控机制，并通过Western blot、免疫沉淀、免疫荧光、GST pull-down实验和救援实验进一步验证。结果我们在ESCC转移患者的肿瘤组织中观察到RCN2高表达，这与转移风险高和生存期差相关。蛋白磷酸酶2 a （PP2A）的催化亚基PPP2CA和泛素蛋白连接酶E3组分n -识别蛋白5 （UBR5）被确定为新的RCN2功能相互作用物。机制上，RCN2促进PPP2CA泛素化和降解依赖于UBR5的HECT结构域，从而激活PI3K-AKT信号通路。此外，激活的RCN2-PPP2CA-PI3K-AKT轴在ESCC临床标本中得到验证。最后，在皮下和肺转移模型中，靶向抑制RCN2与CDDP治疗协同抑制肿瘤生长和转移。总之，这些发现表明RCN2是ESCC转移和CDDP耐药的新驱动因素。RCN2可能是ESCC的一个有希望的治疗靶点。

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分钟内获得全文求助全文

来源期刊

Drug Resistance Updates 医学-药学

CiteScore

26.20

自引率

11.90%

发文量

审稿时长

29 days

期刊介绍： Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research