RIP3 激活剂 C8 可调节由 p62 介导的自噬通量,并促进人胃癌细胞的免疫原性细胞死亡。

IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-11-03 DOI:10.1016/j.bioorg.2024.107937
Xiaojie Liu, Yubin Jin, Mengli Zhang, Yanhe Jin, Jie Cao, Hangqi Dong, Xiangjing Fu, Cheng-Yun Jin
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引用次数: 0

摘要

人们对研究不仅能杀死癌细胞,还能刺激免疫系统的抗肿瘤药物越来越感兴趣,其中坏死是一种经典的免疫原性细胞死亡形式。在我们的研究中,我们发现通过靶向 RIP3,Jaspine B 衍生物 C8 可诱导坏死并引发细胞死亡,而这种效应可通过敲除 RIP3 而逆转。此外,RIP3还能启动自噬,并与p62结合抑制自噬通量。此外,RIP3 介导的自噬过程会通过 p62/Keap1 复合物的形成激活 Nrf2 信号通路。早期自噬抑制剂可通过阻碍 p62 的积累和抑制 Nrf2 的激活来增强坏死,而晚期自噬抑制剂则可部分阻止 C8 诱导的坏死。值得注意的是,C8 诱导的免疫原性细胞死亡并不影响肿瘤免疫。总之,C8 可作为一种 RIP3 激活剂抑制胃癌的发展。激活后,RIP3 通过 RIP3/p62/Keap1 轴调节 p62 介导的自噬通量和 Nrf2 信号通路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The RIP3 activator C8 regulates the autophagy flux mediated by p62 and promotes the immunogenic form of cell death in human gastric cancer cells.

There has been growing interest in investigating anti-tumor drugs that not only kill cancer cells but also stimulate the immune system, among them, necroptosis is a classical immunogenic form of cell death. In our study, we discovered that by targeting RIP3, Jaspine B derivative C8 induces necroptosis and initiates cell death, and this effect can be reversed by knockout of RIP3. Furthermore, RIP3 initiates autophagy and binds to p62 to inhibit autophagic flux. Additionally, the autophagy process mediated by RIP3 activates the Nrf2 signaling pathway via the formation of the p62/Keap1 complex. Early autophagy inhibitors enhance necroptosis by impending the accumulation of p62 and restraining the activation of Nrf2, whereas late autophagy inhibitors partially prevent C8-induced necroptosis. Notably, the immunogenic form of cell death induced by C8 did not affect tumor immunity. Overall, C8 functions as a RIP3 activator to suppress the development of gastric cancer. Upon activation, RIP3 regulates p62-mediated autophagic flux and the Nrf2 signaling pathway through the RIP3/p62/Keap1 axis.

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来源期刊
Bioorganic Chemistry
Bioorganic Chemistry 生物-生化与分子生物学
CiteScore
9.70
自引率
3.90%
发文量
679
审稿时长
31 days
期刊介绍: Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.
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