Calcium Channel Blocker Nifedipine Suppresses Colorectal Cancer Progression and Immune Escape by Preventing NFAT2 Nuclear Translocation
Calcium Channel Blocker Nifedipine Suppresses Colorectal Cancer Progression and Immune Escape by Preventing NFAT2 Nuclear Translocation
复制标题
钙通道阻滞剂硝苯地平通过阻止 NFAT2 核易位抑制结直肠癌进展和免疫逃逸
DOI：
10.1016/j.celrep.2020.108327
复制
发表时间：
2020
期刊：
影响因子：
8.8
通讯作者：
Zhao Liang
中科院分区：
文献类型：
--
作者：
Wu Ling;Lin Weihao;Liao Qing;Wang Hui;Lin Chuang;Tang Lihua;Lian Weidong;Chen Zetao;Li Kaitao;Xu Lijun;Zhou Rui;Ding Yanqing;Zhao Liang
钙通道的异常激活已被证明在肿瘤的发生和发展中起着至关重要的作用。然而，针对钙通道的抑制剂在肿瘤进展和免疫调节中的作用仍不清楚，其临床应用仍然有限。我们发现，硝苯地平（NIFE），钙通道阻滞剂，抑制钙内流损害活化T细胞核因子2（NFAT 2）的去磷酸化，激活和核转位，从而阻止下游信号分子的转录激活，抑制结直肠癌（CRC）的增殖和转移。此外，NIFE降低CRC细胞上程序性死亡配体1（PD-L1）和CD 8 +T细胞上程序性死亡-1（PD-1）的表达，并重新激活肿瘤免疫监测，这可能刺激或增强基于PD-1的抗肿瘤免疫治疗。我们的研究结果提供了直接证据，表明NIFE是一种通过影响肿瘤本身和肿瘤免疫来治疗晚期CRC患者的有希望的临床疗法。NIFE可能是一种有前途的治疗选择，以提高免疫检查点阻断治疗CRC的有效性。
Abnormal activation of calcium channels has been shown to play crucial roles in tumor occurrence and development. However, the role of inhibitors targeting calcium channels in tumor progression and immune regulation remains unclear, and their clinical applications are still limited. We show that nifedipine (NIFE), a calcium channel blocker, inhibits calcium influx to impair nuclear factor of activated T cell 2 (NFAT2) dephosphorylation, activation, and nuclear translocation, thus preventing transcriptional activation of downstream signaling molecules to suppress colorectal cancer (CRC) proliferation and metastasis. In addition, NIFE decreases expression of programmed death-ligand 1 (PD-L1) on CRC cells and programmed death-1 (PD-1) on CD8+T cells and reactivates tumor immune monitoring, which may stimulate or enhance PD-1-based antitumor immunotherapy. Our findings provide direct evidence that NIFE is a promising clinical therapy to treat patients with advanced CRC by affecting the tumor itself and tumor immunity. NIFE may be a promising therapeutic option to enhance effectiveness of immune checkpoint blockade therapy in CRC.