Anti-allergic drug azelastine suppresses colon tumorigenesis by directly targeting ARF1 to inhibit IQGAP1-ERK-Drp1-mediated mitochondrial fission.
Anti-allergic drug azelastine suppresses colon tumorigenesis by directly targeting ARF1 to inhibit IQGAP1-ERK-Drp1-mediated mitochondrial fission.
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抗过敏药物氮卓斯汀通过直接靶向ARF1抑制IQGAP1-ERK-Drp1介导的线粒体裂变抑制结肠肿瘤发生
作者：
Hu HF;Xu WW;Li YJ;He Y;Zhang WX;Liao L;Zhang QH;Han L;Yin XF;Zhao XX;Pan YL;Li B;He QY
本研究旨在从 FDA 批准的非癌症药物中筛选新型抗癌策略，并确定结直肠癌 (CRC) 的潜在生物标志物和治疗靶点。方法：对包含 1056 种 FDA 批准药物的库进行抗癌药物筛选。 WST-1、集落形成、流式细胞术和肿瘤异种移植测定用于确定氮卓斯汀的抗癌作用。进行定量蛋白质组学、共聚焦成像、蛋白质印迹和 JC-1 测定来检查对线粒体途径的影响。通过 DARTS、WST-1、Biacore 和肿瘤异种移植试验对氮卓斯汀的靶蛋白进行了分析和确认。使用免疫组织化学、功能获得和丧失实验、WST-1、集落形成、免疫沉淀和肿瘤异种移植测定来检查ARF1在结肠肿瘤发生中的功能和临床意义。结果：目前的抗过敏药物氮卓斯汀在体外和体内对CRC细胞增殖具有显着的抑制作用，但对ARF1缺陷或ARF1-T48S突变细胞没有作用。 ARF1 被确定为氮卓斯汀的直接靶标。 ARF1 高表达与 CRC 晚期和生存率低相关。 ARF1 通过与 IQGAP1 相互作用以及随后通过增强 IQGAP1 与 MEK 和 ERK 的相互作用激活 ERK 信号和线粒体裂变来促进结肠肿瘤发生。从机制上讲，氮卓斯汀与 ARF1 中的 Thr-48 结合并抑制其活性，从而降低 Drp1 磷酸化。这反过来又通过阻断 IQGAP1-ERK 信号传导来抑制线粒体裂变并抑制结肠肿瘤发生。结论：这项研究提供了第一个证据，表明氮卓斯汀可能是治疗 CRC 的新疗法。 ARF1 促进结肠肿瘤发生，是 CRC 中一个有前途的生物标志物和治疗靶点。
This study aimed to screen novel anticancer strategies from FDA-approved non-cancer drugs and identify potential biomarkers and therapeutic targets for colorectal cancer (CRC). Methods: A library consisting of 1056 FDA-approved drugs was screened for anticancer agents. WST-1, colony-formation, flow cytometry, and tumor xenograft assays were used to determine the anticancer effect of azelastine. Quantitative proteomics, confocal imaging, Western blotting and JC-1 assays were performed to examine the effects on mitochondrial pathways. The target protein of azelastine was analyzed and confirmed by DARTS, WST-1, Biacore and tumor xenograft assays. Immunohistochemistry, gain- and loss-of-function experiments, WST-1, colony-formation, immunoprecipitation, and tumor xenograft assays were used to examine the functional and clinical significance of ARF1 in colon tumorigenesis. Results: Azelastine, a current anti-allergic drug, was found to exert a significant inhibitory effect on CRC cell proliferation in vitro and in vivo, but not on ARF1-deficient or ARF1-T48S mutant cells. ARF1 was identified as a direct target of azelastine. High ARF1 expression was associated with advanced stages and poor survival of CRC. ARF1 promoted colon tumorigenesis through its interaction with IQGAP1 and subsequent activation of ERK signaling and mitochondrial fission by enhancing the interaction of IQGAP1 with MEK and ERK. Mechanistically, azelastine bound to Thr-48 in ARF1 and repressed its activity, decreasing Drp1 phosphorylation. This, in turn, inhibited mitochondrial fission and suppressed colon tumorigenesis by blocking IQGAP1-ERK signaling. Conclusions: This study provides the first evidence that azelastine may be novel therapeutics for CRC treatment. ARF1 promotes colon tumorigenesis, representing a promising biomarker and therapeutic target in CRC.
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