Qian Chunmei, Zhang Xing, Tian Yu-Shi, Yuan Lin, Wei Qiao, Yang Yifu, Xu Midie, Wang Xiaoyu, Sun Menghong
Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0871, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jan 10. doi: 10.1007/s00210-024-03765-6.
Esophageal carcinoma is a highly prevalent malignancy worldwide. The present study aimed to investigate the mechanism by which the natural compound coptisine affects pyroptosis in esophageal squamous cell carcinoma (ESCC). The expression of c-Met in ESCC patients was assessed by immunohistochemical analysis of tissue microarrays. Natural drugs that bind to c-Met were identified by screening and molecular docking. The effect of coptisine on the proliferation of ESCC cells was detected by CCK-8 and colony formation assays. Cell cycle progression and cell apoptosis were detected by flow cytometry. The levels of mRNAs related to pyroptosis and miR-21 after coptisine treatment were assessed via real-time quantitative PCR. The effect of pyroptosis was evaluated by reactive oxygen species level detection and transmission electron microscopy (TEM) analysis. The expression of proteins related to pyroptosis and the HGF/c-Met pathway was detected by western blotting. A xenograft tumor model was established, and the inhibitory effect of coptisine was evaluated by observing tumor growth. The results showed that the highly expressed protein c-Met in esophageal cancer could bind with coptisine. Coptisine inhibited c-Met phosphorylation and proliferation in ESCC cells. Furthermore, coptisine inhibited the expression of downstream proteins of the HGF/c-Met signaling pathway and induced ROS generation. Tumor xenograft experiments demonstrated that coptisine effectively inhibited tumor growth by reducing the levels of pyroptosis-associated proteins. In conclusion, these findings indicate that inhibition of the HGF/c-Met signaling pathway suppresses pyroptosis to enhance the antitumor effect of coptisine in ESCC and support the potential use of coptisine for EC treatment.
食管癌是一种在全球范围内高度流行的恶性肿瘤。本研究旨在探讨天然化合物黄连碱影响食管鳞状细胞癌（ESCC）细胞焦亡的机制。通过组织芯片的免疫组化分析评估ESCC患者中c-Met的表达。通过筛选和分子对接鉴定与c-Met结合的天然药物。采用CCK-8和集落形成试验检测黄连碱对ESCC细胞增殖的影响。通过流式细胞术检测细胞周期进程和细胞凋亡。通过实时定量PCR评估黄连碱处理后与焦亡相关的mRNA和miR-21的水平。通过活性氧水平检测和透射电子显微镜（TEM）分析评估焦亡的影响。通过蛋白质印迹法检测与焦亡和HGF/c-Met途径相关的蛋白质表达。建立异种移植肿瘤模型，通过观察肿瘤生长评估黄连碱的抑制作用。结果表明，食管癌中高表达的蛋白c-Met可与黄连碱结合。黄连碱抑制ESCC细胞中c-Met的磷酸化和增殖。此外，黄连碱抑制HGF/c-Met信号通路下游蛋白的表达并诱导ROS生成。肿瘤异种移植实验表明，黄连碱通过降低焦亡相关蛋白的水平有效抑制肿瘤生长。总之，这些发现表明抑制HGF/c-Met信号通路可抑制焦亡，增强黄连碱在ESCC中的抗肿瘤作用，并支持黄连碱在食管癌治疗中的潜在应用。
