RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
一种介导免疫破坏衰老癌细胞的抗生素
英文原题：An antibiotic that mediates immune destruction of senescent cancer cells.
查看英文原题
An antibiotic that mediates immune destruction of senescent cancer cells.
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中文摘要
消除衰老细胞的药物，即senolytics，与促衰老癌症疗法联合使用时可以发挥强大作用。通过基于CRISPR/Cas9的遗传筛选，我们在此鉴定出SLC25A23是衰老癌细胞的一个脆弱靶点。抑制SLC25A23会破坏细胞钙稳态，损害氧化磷酸化，并干扰氧化还原信号传导，导致衰老细胞死亡。这些效应可通过盐霉素（一种阳离子离子载体抗生素）复制。盐霉素在衰老细胞中引发一种类似焦亡-凋亡-坏死性凋亡（PAN）optosis的细胞死亡，包括凋亡和两种形式的免疫原性细胞死亡：坏死性凋亡和焦亡。
值得注意的是，我们观察到盐霉素处理或SLC25A23抑制会升高活性氧，通过Jun N-末端蛋白激酶（JNK）通路激活上调死亡受体5。
我们表明，死亡受体5（DR5）激动性抗体与盐霉素的组合是一种强效的senolytic鸡尾酒。我们提供证据表明，这种药物组合可引发强效的自然杀伤（NK）细胞和CD8+ T细胞介导的对衰老癌细胞的免疫破坏，由焦亡性细胞因子白细胞介素18（IL18）介导。
展开英文摘要原文
Drugs that eliminate senescent cells, senolytics, can be powerful when combined with prosenescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation, and interferes with redox signaling, leading to death of senescent cells.
These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a pyroptosis-apoptosis-necroptosis (PAN)optosis-like cell death in senescent cells, including apoptosis and two forms of immunogenic cell death: necroptosis and pyroptosis.
Notably, we observed that salinomycin treatment or SLC25A23 suppression elevates reactive oxygen species, upregulating death receptor 5 via Jun N-terminal protein kinase (JNK) pathway activation.
We show that a combination of a death receptor 5 (DR5) agonistic antibody and salinomycin is a robust senolytic cocktail.
We provide evidence that this drug combination provokes a potent natural killer (NK) and CD8+ T cell-mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine interleukin 18 (IL18).
论文信息
- 作者
- Casagrande Raffi G、Chen J、Feng X、Chen Z、Lieftink C、Deng S、Mo J、Zeng C
- 单位
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.Netherlands
- 期刊
- Proceedings of the National Academy of Sciences of the United States of America2024 Dec 24
- 原文标识
- PubMed 39693343 · DOI 10.1073/pnas.2417724121
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