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CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
NK 细胞效应程序的表观遗传激活与 caspase-8 依赖性凋亡介导 LGP 在 NSCLC 中的抗肿瘤活性
英文原题：Epigenetic activation of NK-cell effector programs and caspase-8-dependent apoptosis mediates the antitumor activity of LGP in NSCLC.
查看英文原题
Epigenetic activation of NK-cell effector programs and caspase-8-dependent apoptosis mediates the antitumor activity of LGP in NSCLC.
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研究概要
LGP 发挥双重抗肿瘤效应，其特征为增强 NK 细胞活化以及增加肿瘤细胞对 caspase-8 依赖性外源性凋亡的敏感性。这些协同的免疫相关效应和凋亡增敏效应凸显了 LGP 用于治疗 NSCLC 的治疗潜力。
研究思路结论见上方概要
背景
有效激活自然杀伤（NK）细胞细胞毒作用及 caspase-8 依赖的外源性凋亡，仍然是非小细胞肺癌（NSCLC）面临的一大挑战。肿瘤微环境中调控 NK 细胞功能的表观遗传学机制目前了解甚少，且鲜有作为治疗靶点。
方法
在体外人肺癌 A549 细胞和 A549 异种移植小鼠模型中评估了 Li-Ginseng Powder (LGP) 的抗肿瘤活性，LGP 是一种经特殊加工、富含稀有人参皂苷 (Rh4、Rg3、Rg5、Rk1 和 Rk3) 的人参制剂。通过流式细胞术、免疫印迹和免疫组织化学评估了 NK 细胞浸润和活化。进行全基因组亚硫酸氢盐测序 (WGBS) 以分析 DNA 甲基化变化。在体外检测了 LGP 人参皂苷 (LGG) 对肿瘤细胞凋亡和死亡受体信号传导的影响。
结果
LGP 显著抑制肿瘤生长，并增强全身及瘤内 NK 细胞活化。NK 细胞效应基因（包括 Ncr1、Gzmb、Nktr 和 Itgal）的启动子去甲基化与 NK 细胞浸润和活化增加、颗粒介导的细胞毒性升高以及 IFN- 信号增强相关。与此同时，LGP 治疗诱导了 caspase-8 依赖性凋亡，并伴有肿瘤组织中膜死亡受体及其配体、FADD 和 procaspase-8 表达升高。在体外，LGG 上调了这些凋亡起始蛋白，并在 A549 细胞中触发 caspase-8 活化，且不依赖于启动子甲基化改变。总体而言，这些免疫相关及肿瘤内在的反应共同促成了强效的肿瘤抑制，并具有良好的全身安全性。
展开英文摘要原文
BACKGROUND
Effective activation of natural killer (NK) cell cytotoxicity and caspase-8-dependent extrinsic apoptosis remains a major challenge in non-small cell lung cancer (NSCLC). Epigenetic mechanisms regulating NK cell function within the tumor microenvironment are poorly understood and rarely targeted therapeutically.
METHODS
The antitumor activity of Li-Ginseng Powder (LGP), a specifically processed Panax ginseng formulation enriched in rare ginsenosides (Rh4, Rg3, Rg5, Rk1, and Rk3), was evaluated in human lung cancer A549 cells and A549 xenograft mouse models. NK cell infiltration and activation were assessed by flow cytometry, immunoblotting, and immunohistochemistry. Whole-genome bisulfite sequencing (WGBS) was performed to analyze DNA methylation changes. The effects of LGP ginsenosides (LGG) on tumor cell apoptosis and death receptor signaling were examined in vitro.
RESULTS
LGP significantly suppressed tumor growth and enhanced systemic and intratumoral NK cell activation. Promoter demethylation of NK cell effector genes, including Ncr1, Gzmb, Nktr, and Itgal, was associated with increased NK cell infiltration and activation, elevated granule-mediated cytotoxicity, and enhanced IFN- signaling. In parallel, LGP treatment induced caspase-8-dependent apoptosis associated with increased expression of membrane death receptors, their ligands, FADD, and procaspase-8 in tumor tissues. In vitro, LGG upregulated these apoptosis-initiating proteins and triggered caspase-8 activation in A549 cells independent of promoter methylation changes. Collectively, these immune-associated and tumor-intrinsic responses contributed to robust tumor suppression with a favorable systemic safety profile.
CONCLUSIONS
LGP exerts dual antitumor effects characterized by enhanced NK-cell activation and increased sensitivity of tumor cells to caspase-8-dependent extrinsic apoptosis. These coordinated immune-associated and apoptosis-sensitizing effects underscore the therapeutic potential of LGP for the treatment of NSCLC.
论文信息
- 作者
- Li GA、Jin XH、Zhu ZX、Wang YN、Zhao ZH、Liu WY、Zhang SY、Cai XH
- 单位
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun, 130012, China.China
- 期刊
- Journal of ginseng research2026 Sep
- 原文标识
- PubMed 42719419 · DOI 10.1016/j.jgr.2026.101104
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