Leukotriene receptor antagonists enhance HCC treatment efficacy by inhibiting ADAMs and suppressing MICA shedding.
Leukotriene receptor antagonists enhance HCC treatment efficacy by inhibiting ADAMs and suppressing MICA shedding.
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DOI：
10.1007/s00262-020-02660-2
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Yoshida H
中科院分区：
文献类型：
--
作者：
Arai J;Goto K;Otoyama Y;Nakajima Y;Sugiura I;Kajiwara A;Tojo M;Ichikawa Y;Uozumi S;Shimozuma Y;Uchikoshi M;Sakaki M;Nozawa H;Nakagawa R;Muroyama R;Kato N;Yoshida H
在我们之前的全基因组关联研究中，我们证明了MHC i类相关链A （MICA）与慢性丙型肝炎患者肝细胞癌（HCC）发展之间的关联。通过减少MICA脱落酶增加癌细胞中膜结合MICA （mMICA）促进自然杀伤（NK）细胞介导的细胞毒性。我们最近的研究表明，包括ADAM9在内的A崩解素和金属蛋白酶（ADAM）是HCC中的MICA脱落酶，抑制ADAMs可增加mMICA，证明了mMICA- nk靶向治疗的合理性。此外，我们发现regorafenib通过转录和翻译抑制ADAM9。筛选了fda批准的药物库，以寻找更有效的ADAM9抑制剂。流式细胞术检测多种候选药物治疗后mMICA的表达，发现白三烯受体拮抗剂是潜在的ADAM9抑制剂。此外，白三烯受体拮抗剂单独使用或与瑞戈非尼联合使用可上调mMICA，而白三烯C4和D4通过ADAM9功能下调mMICA。我们的研究表明，白三烯受体拮抗剂可以作为肝癌免疫控制和抑制ADAM9的新药。此外，白三烯受体拮抗剂应与传统的多激酶抑制剂联合治疗，以制定治疗策略，提高HCC的管理和治疗效果。本文的在线版本（10.1007/s00262-020-02660-2）包含补充材料，仅供授权用户使用。
In our previous genome-wide association study, we demonstrated the association between MHC class I-related chain A (MICA) and hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. Increasing membrane-bound MICA (mMICA) in cancer cells by reducing MICA sheddases facilitates natural killer (NK) cell-mediated cytotoxicity. Our recent study clarified that A disintegrin and metalloproteases (ADAM), including ADAM9, are MICA sheddases in HCC, and that the suppression of ADAMs increases mMICA, demonstrating the rationality of mMICA-NK targeted therapy. Furthermore, we showed that regorafenib suppresses ADAM9 transcriptionally and translationally. A library of FDA-approved drugs was screened for more efficient inhibitors of ADAM9. Flow cytometry evaluation of the expression of mMICA after treatment with various candidate drugs identified leukotriene receptor antagonists as potential ADAM9 inhibitors. Furthermore, leukotriene receptor antagonists alone or in combination with regorafenib upregulated mMICA, which was in turn downregulated by leukotriene C4 and D4 via ADAM9 function. Our study demonstrates that leukotriene receptor antagonists could be developed as novel drugs for immunological control and suppression of ADAM9 in HCC. Further, leukotriene receptor antagonists should be explored as combination therapy partners with conventional multi-kinase inhibitors for developing therapeutic strategies with enhanced efficacies for HCC management and treatment. The online version of this article (10.1007/s00262-020-02660-2) contains supplementary material, which is available to authorized users.
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影响因子：
4.6
作者：
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