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Benproperine, an ARPC2 inhibitor, suppresses cancer cell migration and tumor metastasis
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
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.