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
通过特异性阻断 KCa3.1 通道减少 Ca(2+) 内流可优化 NK 细胞对 T-ALL Jurkat 细胞的细胞毒性活性
英文原题：Reduction of Ca(2+) Entry by a Specific Block of KCa3.1 Channels Optimizes Cytotoxic Activity of NK Cells against T-ALL Jurkat Cells.
查看英文原题
Reduction of Ca(2+) Entry by a Specific Block of KCa3.1 Channels Optimizes Cytotoxic Activity of NK Cells against T-ALL Jurkat Cells.
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中文摘要
NK 细胞通过脱颗粒介导的杀伤机制依赖于钙库操纵性钙内流（SOCE），并在中等程度的细胞内 Ca2+ 升高时达到最佳状态，因此部分阻断 SOCE 可优化杀伤过程。
在本研究中，我们测试了 KCa3.1 通道选择性阻断剂 NS6180 对来自健康供体的 NK 细胞和 NK-92 细胞针对 T-ALL 细胞系 Jurkat 的 SOCE 及杀伤效率的影响。膜片钳分析显示，仅四分之一的静息 NK 细胞功能性表达 KCa3.1 电流，而在白介素 15 和 2 激活后其增加 3 倍。尽管如此，阻断 KCa3.1 显著降低了由 IL-15 或靶细胞识别诱导的 SOCE 和细胞内 Ca2+ 升高。NS6180（1 μM）在与 Jurkat 细胞共培养的零时降低 NK 脱颗粒，但已在 1 小时后，脱颗粒达到与对照相同的水平。通过流式细胞术和共聚焦显微镜监测靶细胞死亡表明，NS6180 在与 Jurkat 细胞共培养 1 小时后显著提高了 NK 细胞的杀伤能力，并增加了具有凋亡和坏死标志物的 Jurkat 细胞比例。
我们的数据证明 NK 细胞中 SOCE 对 KCa3.1 活性有强烈依赖性，并且 KCa3.1 特异性阻断可改善 NK 细胞毒性。
展开英文摘要原文
Degranulation mediated killing mechanism by NK cells is dependent on store-operated Ca 2+ entry (SOCE) and has optimum at moderate intracellular Ca 2+ elevations so that partial block of SOCE optimizes the killing process. In this study, we tested the effect of the selective blocker of KCa3. 1 channel NS6180 on SOCE and the killing efficiency of NK cells from healthy donors and NK-92 cells against T-ALL cell line Jurkat. Patch-clamp analysis showed that only one-quarter of resting NK cells functionally express KCa3. 1 current, which increases 3-fold after activation by interleukins 15 and 2.
Nevertheless, blockage of KCa3. 1 significantly reduced SOCE and intracellular Ca 2+ rise induced by IL-15 or target cell recognition. NS6180 (1 μM) decreased NK degranulation at zero time of coculture with Jurkat cells but already after 1 h, the degranulation reached the same level as in the control.
Monitoring of target cell death by flow cytometry and confocal microscopy demonstrated that NS6180 significantly improved the killing ability of NK cells after 1 h in coculture with Jurkat cells and increased the Jurkat cell fraction with apoptotic and necrotic markers.
Our data evidence a strong dependence of SOCE on KCa3. 1 activity in NK cells and that KCa3. 1 specific block can improve NK cytotoxicity.
论文信息
- 作者
- Olivas-Aguirre M、Cruz-Aguilar LH、Pottosin I、Dobrovinskaya O
- 单位
- Laboratory of Immunobiology and Ionic Transport Regulation, University Center for Biomedical Research, University of Colima, Colima 28045, Mexico.Mexico
- 文献类型
- 非美国政府资助研究
- 期刊
- Cells2023 Aug 15
- 原文标识
- PubMed 37626875 · DOI 10.3390/cells12162065
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