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  • br Carpizo DR D Angelica M

    2022-07-06


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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. 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.
    1. Introduction
    In solid tumors, cytostatic drugs have been shown to effectively inhibit the growth of cancer cells but have not been efficacious on cancer metastasis [1]. Metastasis is the leading cause of cancer-related death [2,3] and cancer cell migration is an essential stage of metastasis [4,5]. Therefore, the unmet needs of anti-cancer drug discovery include identifying agents that prevent or block metastasis but that are also safe, selective, and effective. Oncogenic kinase inhibitors targeting signal transduction in cell migration lead to resistance due to highly redundant and bypassable signaling pathways [6]. To overcome drug resistance, migrastatics targeting the modulators or effectors of cancer cell migration and invasion have been proposed as a promising ther-apeutic strategy for treatment of solid tumors [6,7]. Target mechanisms for migrastatics include actin polymerization and actomyosin-mediated contractility [7]. Remodeling of the cytoskeleton plays a pivotal role in