Taraxasterol regulates p53 transcriptional activity to inhibit pancreatic cancer by inducing MDM2 ubiquitination degradation.

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2024-12-07 DOI:10.1016/j.phymed.2024.156298

Anna Han, Jiajing Liu, Pan Du, Wenxuan Li, Haiyan Quan, Zhenhua Lin, Liyan Chen

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引用次数: 0

Abstract

Background: Pancreatic cancer (PC) is a malignant tumor with complex development mechanisms and a poor prognosis. Taraxasterol (TAX), a pentacyclic triterpenoid plant sterol derived from Taraxacum mongolicum, has multiple biological activities including an anti-tumor effect. However, the mechanism by which TAX exerts its anticancer effects in PC remains unclear.

Purpose: This study aimed to elucidate the molecular mechanism by which TAX suppresses the proliferation of PC.

Methods: The intersection of TAX and PC targets was obtained through network pharmacology. RNA-seq was used to identify TAX-induced differentially expressed genes in PC. Molecular docking, CETSA, western blot analysis, and qRT-PCR were performed to confirm the effectiveness of targets. The influence of TAX on PC was assessed by analyzing proliferation, apoptosis, and the cell cycle via MTT assay, colony formation assay, and flow cytometry, respectively. Co-IP assay and immunofluorescence assay were used to evaluate the effect of TAX on targeted genes. A nude mouse xenograft model was constructed to determine the inhibitory effects of TAX on PC in vivo.

Results: TAX suppressed PC cell proliferation by promoting apoptosis and inducing cell cycle arrest in vitro and in vivo. Mechanistically, TAX interacted with MDM2, a critical regulator of proliferation, and decreased its stability by inducing ubiquitin-mediated degradation, which facilitates the nuclear translocation of p53 and downregulation of CXCL5 transcription, ultimately suppressing PC cell proliferation.

Conclusion: MDM2/p53/CXCL5 is the key pathway of TAX inhibiting the proliferation of PC cells.

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蒲公英甾醇通过诱导 MDM2 泛素化降解来调节 p53 的转录活性，从而抑制胰腺癌。

背景：胰腺癌（PC）是一种发展机制复杂、预后不良的恶性肿瘤。蒲公英甾醇（TAX）是从蒲公英中提取的一种五环三萜类植物甾醇，具有多种生物活性，包括抗肿瘤作用。目的：本研究旨在阐明 TAX 抑制 PC 增殖的分子机制：方法：通过网络药理学获得TAX与PC靶点的交叉点。RNA-seq用于鉴定TAX诱导的PC差异表达基因。进行了分子对接、CETSA、Western印迹分析和qRT-PCR，以确认靶点的有效性。通过MTT试验、集落形成试验和流式细胞术分析增殖、凋亡和细胞周期，分别评估了TAX对PC的影响。Co-IP 分析和免疫荧光分析用于评估 TAX 对靶基因的影响。通过构建裸鼠异种移植模型来确定TAX对体内PC的抑制作用：结果：在体外和体内，TAX通过促进细胞凋亡和诱导细胞周期停滞来抑制PC细胞增殖。从机理上讲，TAX 与增殖的关键调控因子 MDM2 相互作用，通过诱导泛素介导的降解降低其稳定性，从而促进 p53 的核转位和 CXCL5 的转录下调，最终抑制 PC 细胞的增殖：MDM2/p53/CXCL5是TAX抑制PC细胞增殖的关键途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

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.