Curcumol promotes ferroptosis of colon cancer by targeting the ubiquitination and degradation of GPX4

IF 3.3 3区医学 Q1 INTEGRATIVE & COMPLEMENTARY MEDICINE

Journal of Traditional and Complementary Medicine Pub Date : 2024-08-21 DOI:10.1016/j.jtcme.2024.08.006

Wuxia Zhao , Qiuying Yan , Lianfang Liu , Dahai Hou , Dongyang Xiang , Dongxin Tang , Liu Li , Weixing Shen , Weiwei Tao , Haibo Cheng , Dongdong Sun

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引用次数: 0

Abstract

Background and aim

Colon cancer (CC) is one of the common malignant tumors in the digestive tract, the prognosis of CC patients has never been satisfying. A Ferrous-dependent form that regulates cell death, plays a key role in cancer development. As a core regulator of ferroptosis, GPX4 has become a potential molecular target for the development of antitumor drugs. Curcumol (Cur), a sesquiterpene natural product, it has significant anti-tumor effect. However, whether Cur mediates ferroptosis in colon cancer and its mechanism are still unclear. This study aimed to investigate the underlying mechanisms of Cur anti-tumor.

Experimental procedure

By investigating the Cancer Genome Atlas (TCGA) database and tissue immunofluorescence staining was also used to detect the levels of GPX4 protein in CC and matching paracancerous tissues. The anti-CC and pro-ferroptosis effects of Cur were detected in the vivo and vitro experiment. The interaction between Cur and GPX4 was predicted. In addition, the potential mechanism of Cur anti-CC was further discussed. Co-immunoprecipitation was used to confirm Cur-mediated GPX4 ubiquitination.

Results and conclusion

GPX4 was upregulated in CC tissue and was correlated with poor survival of patients. Cur inhibited the proliferation of CC cells, accompanied by regulating Fe²⁺ overload, reactive oxygen species (ROS) formation, malondialdehyde (MDA) production and superoxide dismutase (SOD) consumption. Furthermore, GPX4 was predicted and verified as the direct target of Cur by molecular docking and structure-based virtual prediction. Meanwhile, Cur could promote the ubiquitination-mediated degradation of GPX4, induce ferroptosis in CC cells and regulate the expression of ferroptosis-related protein FTH1 and TfR1. In addition, when GPX4 was overexpressed (GPX4-OE), the inhibitory effect of Cur on the expression of GPX4 and ferroptosis-related protein FTH1 and the promotion of TfR1 expression were abolished. Cur could inhibit CC by increasing the ubiquitination degradation level of GPX4 to induce ferroptosis in CC cells.

Abstract Image

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姜黄醇通过靶向 GPX4 的泛素化和降解促进结肠癌的铁变态反应

背景与目的结肠癌（colorectal cancer， CC）是消化道常见的恶性肿瘤之一，其预后一直不理想。一种调节细胞死亡的铁依赖形式在癌症发展中起着关键作用。GPX4作为铁下垂的核心调控因子，已成为开发抗肿瘤药物的潜在分子靶点。Curcumol （Cur）是一种倍半萜类天然产物，具有显著的抗肿瘤作用。然而，Cur是否介导结肠癌铁下垂及其机制尚不清楚。本研究旨在探讨其抗肿瘤作用机制。通过肿瘤基因组图谱（Cancer Genome Atlas， TCGA）数据库和组织免疫荧光法检测GPX4蛋白在CC及配对癌旁组织中的表达水平。在体内和体外实验中检测了Cur的抗cc和促铁下垂作用。预测了Cur与GPX4的相互作用。此外，还进一步探讨了氯化铜抗氯化铜的潜在机理。共免疫沉淀法证实了curr介导的GPX4泛素化。结果与结论ongpx4在CC组织中表达上调，与患者生存不良相关。Cur抑制CC细胞增殖，同时调节Fe2+过载、活性氧（ROS）形成、丙二醛（MDA）产生和超氧化物歧化酶（SOD）消耗。通过分子对接和基于结构的虚拟预测，预测并验证了GPX4是Cur的直接靶点。同时，Cur可促进泛素化介导的GPX4降解，诱导CC细胞铁沉，调节铁沉相关蛋白FTH1和TfR1的表达。此外，当GPX4过表达（GPX4- oe）时，Cur对GPX4和铁凋亡相关蛋白FTH1表达的抑制作用以及对TfR1表达的促进作用被取消。Cur可以通过提高GPX4的泛素化降解水平来抑制CC，诱导CC细胞铁凋亡。

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

Journal of Traditional and Complementary Medicine Medicine-Complementary and Alternative Medicine

CiteScore

9.30

自引率

6.70%

发文量

审稿时长

66 days

期刊介绍： eJTCM is committed to publish research providing the biological and clinical grounds for using Traditional and Complementary Medical treatments as well as studies that demonstrate the pathophysiological and molecular/biochemical bases supporting the effectiveness of such treatments. Review articles are by invitation only. eJTCM is receiving an increasing amount of submission, and we need to adopt more stringent criteria to select the articles that can be considered for peer review. Note that eJTCM is striving to increase the quality and medical relevance of the publications.

文献相关原料

公司名称

产品信息

上海源叶

Curcumol | ≥98%

￥111.00~￥31478.18

索莱宝

SOD assay kit

索莱宝

MDA assay kit