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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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.

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Curcumol |≥98%
¥111.00~¥31478.18
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SOD assay kit
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MDA assay kit
来源期刊
Journal of Traditional and Complementary Medicine
Journal of Traditional and Complementary Medicine Medicine-Complementary and Alternative Medicine
CiteScore
9.30
自引率
6.70%
发文量
78
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.
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