Targeting and degradation of OTUB1 by Erianin for antimetastasis in esophageal squamous cell carcinoma.

IF 6.7 1区 医学 Q1 CHEMISTRY, MEDICINAL Phytomedicine Pub Date : 2024-12-01 Epub Date: 2024-08-19 DOI:10.1016/j.phymed.2024.155969
Yuan Zhu, Ningning Kang, Li Zhang, Jianju Tao, Wen Xue, Hui Li, Yingcan Li, Xucai Zheng, Wei He, Junting Ma
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Abstract

Background: Metastasis is a major contributor to mortality in patients with esophageal squamous cell carcinoma (ESCC); effective treatment is currently lacking. Erianin, a bioactive ingredient of traditional Chinese medicine, Dendrobium chrysotoxum, has anti-tumor activity against multiple human tumors. However, the effect and associated underlying mechanism of Erianin on ESCC antimetastasis remain unclear.

Purpose: To investigate the anti-metastatic properties of Erianin in ESCC both in vitro and in vivo and associated molecular mechanisms.

Methods: Wound healing assay, Transwell assay, CCK-8 assay, immunohistochemistry, and lung metastasis mouse model were carried out to examine ESCC cell migration and viability in vitro and in vivo. Drug affinity responsive target stability (DARTS), cellular thermal migration assay (CETSA), molecular docking, and Surface plasmon resonance (SPR) assay were used to confirm Erianin binding to ovarian tumor ubiquitin aldehyde-binding protein 1 (OTUB1) protein. Protein stability assay, cell transfection, and western blotting were used to confirm Erianin-mediated degradation of OTUB1 and Snail via the ubiquitin-proteasome pathway. qRT-PCR and western blotting were used to assess OTUB1expression in ESCC tissues.

Results: Erianin suppressed the migration/invasion of ESCC cells without modulating cell viability in vitro and in vivo, bound to OTUB1 through DARTS, CETSA, and molecular docking, and SPR assay, and enhanced OTUB1 degradation via the ubiquitin-proteasome system. Moreover, Erianin inhibited the ESCC epithelial-mesenchymal transition by enhancing the ubiquitination and degradation of Snail via targeting OTUB1.

Conclusion: Erianin inhibited ESCC metastasis through ubiquitination and degradation of Snail via targeting OTUB1. Our findings suggest Erianin as a novel OTUB1 inhibitor for preventing ESCC metastasis.

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利用 Erianin 靶向和降解食管鳞状细胞癌中的 OTUB1,实现抗转移。
背景:转移是食管鳞状细胞癌(ESCC)患者死亡的主要原因,目前尚缺乏有效的治疗方法。传统中药铁皮石斛中的一种生物活性成分 "二烯酮 "对多种人类肿瘤具有抗肿瘤活性。目的:研究 Erianin 在体外和体内对 ESCC 的抗转移特性及相关分子机制:方法:通过伤口愈合试验、Transwell试验、CCK-8试验、免疫组化和肺转移小鼠模型,研究ESCC细胞在体内和体外的迁移和活力。利用药物亲和力反应靶点稳定性(DARTS)、细胞热迁移试验(CETSA)、分子对接和表面等离子体共振(SPR)试验证实了 Erianin 与卵巢肿瘤泛素醛结合蛋白 1(OTUB1)蛋白的结合。蛋白质稳定性测定、细胞转染和Western印迹法证实了Erianin通过泛素蛋白酶体途径介导的OTUB1和Snail降解:通过DARTS、CETSA、分子对接和SPR检测,Erianin与OTUB1结合,并通过泛素-蛋白酶体系统增强OTUB1的降解。此外,Erianin通过靶向OTUB1增强Snail的泛素化和降解,从而抑制ESCC上皮-间质转化:结论:Erianin通过靶向OTUB1抑制Snail的泛素化和降解,从而抑制ESCC的转移。我们的研究结果表明,Erianin是一种新型的OTUB1抑制剂,可用于预防ESCC转移。
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来源期刊
Phytomedicine
Phytomedicine 医学-药学
CiteScore
10.30
自引率
5.10%
发文量
670
审稿时长
91 days
期刊介绍: Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.
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