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
通过筛选 ADAM9 抑制剂成功鉴定出一种用于肝细胞癌的新型治疗化合物
英文原题：Successful Identification of a Novel Therapeutic Compound for Hepatocellular Carcinoma Through Screening of ADAM9 Inhibitors.
查看英文原题
Successful Identification of a Novel Therapeutic Compound for Hepatocellular Carcinoma Through Screening of ADAM9 Inhibitors.
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研究概要
CCL347 有潜力成为 HCC 的新型治疗药物。
研究思路结论见上方概要
背景
MHC-I类相关链A（MICA）作为自然杀伤组D的配体发挥作用，后者是自然杀伤（NK）细胞上的活化受体，其表达与肝细胞癌（HCC）的发生和进展相关。尽管膜型MICA（mMICA）可激活NK细胞，但由切割酶如解整合素和金属蛋白酶（ADAM）9切割产生的可溶性MICA（sMICA）则抑制NK细胞。因此，通过抑制ADAM9来阻止MICA脱落具有激活癌症免疫的潜力。尽管我们已经发现了若干ADAM抑制剂，但许多抑制剂在不产生细胞毒性的情况下未能充分激活NK细胞，因此，需要新的ADAM9抑制剂候选物。
方法
为识别可用于药物开发的潜在化合物，采用荧光测定法进行了化合物库筛选（共741种化合物）。荧光强度降低的化合物作为命中化合物用于后续分析。分别使用ELISA和流式细胞术评估其对HCC细胞系中sMICA和mMICA的影响。通过将NK细胞与HCC细胞共培养，还评估了NK细胞的细胞毒性。
结果
CCL347，一种具有五个苯环的对称化合物，被鉴定为先导化合物。CCL347显著降低了培养基上清液中的sMICA水平，且细胞毒性可忽略不计。尽管mMICA也有所减少，但CCL347在NK细胞与HCC细胞的共培养中成功增强了NK细胞毒性。
展开英文摘要原文
MATERIALS AND METHODS
To identify possible compounds for drug development, chemical library screening (a total of 741 compounds) was conducted using a fluorescence assay. Compounds with reduced fluorescence intensity were used as hit compounds in a subsequent analysis. Their impact on sMICA and mMICA in HCC cell lines was assessed using ELISA and flow cytometry, respectively. The cytotoxicity of NK cells was also evaluated by co-culturing NK cells with HCC cells.
RESULTS
CCL347, a symmetrical compound with five benzene rings, was identified as a hit compound. CCL347 significantly reduced sMICA levels in the culture medium supernatant with negligible cytotoxicity. Although mMICA was also reduced, CCL347 successfully enhanced NK cell cytotoxicity in co-cultures of NK cells and HCC cells.
CONCLUSION
CCL347 has potential as a novel therapeutic drug for HCC.
论文信息
- 作者
- Ogawa K、Chiba T、Nakamura M、Arai J、Zhang J、Ma Y、Qiang NA、Ao J
- 第一作者单位
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.Japan
- 通讯作者单位
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan; chibatet@chiba-u.jp.Japan
- 期刊
- Anticancer research2023 Mar
- 原文标识
- PubMed 36854524 · DOI 10.21873/anticanres.16249