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  • br de Jong MC Pulitano C Ribero

    2020-08-18


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    Contents lists available at ScienceDirect
    Biochemical Pharmacology
    journal homepage: www.elsevier.com/locate/biochempharm
    Benproperine, an ARPC2 inhibitor, suppresses cancer cell migration and tumor metastasis 
    T
    Yae Jin Yoona,1, Young-Min Hana,1, Jiyeon Choia,c, Yu-Jin Leea, Jieun Yuna, Su-Kyung Leea, Chang Woo Leea, Jong Soon Kanga, Seung-Wook Chia,b, Jeong Hee Moona, Sangku Leea, Dong Cho Hana,b, , Byoung-Mog Kwona,b, a Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Daejeon 34141, Republic of Korea b Korea University of Science and Technology in Korea, Daejeon, Republic of Korea c Department of Biology, Chungnam National University, Daejeon 34134, Republic of Korea
    Keywords:
    Arp2/3 complex
    ARPC2
    Benproperine
    Drug repurposing
    Metastasis 
    Metastasis is the leading cause of cancer mortality and cancer cell migration is an essential stage of metastasis. We identified benproperine (Benp, a clinically used antitussive drug) as an inhibitor of cancer cell migration and an anti-metastatic agent. Benp selectively inhibited cancer cell migration and invasion, which also suppressed metastasis of cancer cells in animal models. 113775-47-6 Actin-related protein 2/3 complex subunit 2 (ARPC2) was identified as a molecular target of Benp by affinity column chromatography with Benp-tagged Sepharose beads. Benp bound directly to ARPC2 in cells, which was validated by pull-down assay using Benp-biotin and label-free biochemical methods such as the drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA). Benp inhibited Arp2/3 function, showing disruption of lamellipodial structure and inhibition of actin polymerization. Unlike Arp2/3 inhibitors, Benp selectively inhibited the migration of cancer cells but not normal cells. ARPC2-knockdown cancer cells showed defective cell migration and suppressed metastasis in an animal model. Therefore, ARPC2 is a potential target for anti-metastatic therapy, and Benp has the clinical potential to block metastasis. Furthermore, Benp is a useful agent for studying the functions of the Arp2/3 complex in cancer cell migration and metastasis.