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Theranostics 2021; 11(4):1828-1844. doi:10.7150/thno.48698 This issue Cite

Research Paper

Anti-allergic drug azelastine suppresses colon tumorigenesis by directly targeting ARF1 to inhibit IQGAP1-ERK-Drp1-mediated mitochondrial fission

Hui-Fang Hu¹, Wen Wen Xu², Yang-Jia Li¹, Yan He², Wei-Xia Zhang¹, Long Liao¹, Qi-Hua Zhang¹, Lei Han², Xing-Feng Yin¹, Xiao-Xu Zhao³, Yun-Long Pan³, Bin Li^1✉, Qing-Yu He^1✉

1. MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University, Guangzhou, China.
2. MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China.
3. MOE Key Laboratory of Tumor Molecular Biology and Department of General Surgery, First-Affiliated Hospital, Jinan University, Guangzhou, China.

✉ Corresponding authors: Prof. Qing-Yu He, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China; Phone/Fax: 86-20-85227039; E-mail: tqyheedu.cn. Prof. Bin Li, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China; Phone/Fax: 86-20-85224372; E-mail: libin2015edu.cn. More

Abstract

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.

Keywords: colorectal cancer, azelastine, drug repurposing, ARF1, mitochondrial fission

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