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

被引：43

作者：

Yoon, Yae Jin ^{[1
]}

Han, Young-Min ^{[1
]}

Choi, Jiyeon ^{[1
,3
]}

Lee, Yu-Jin ^{[1
]}

Yun, Jieun ^{[1
]}

Lee, Su-Kyung ^{[1
]}

Lee, Chang Woo ^{[1
]}

Kang, Jong Soon ^{[1
]}

Chi, Seung-Wook ^{[1
,2
]}

Moon, Jeong Hee ^{[1
]}

Lee, Sangku ^{[1
]}

Han, Dong Cho ^{[1
,2
]}

Kwon, Byoung-Mog ^{[1
,2
]}

机构：

[1] Korea Res Inst Biosci & Biotechnol, Lab Chem Biol & Genom, 125 Gwahakro, Daejeon 34141, South Korea

[2] Korea Univ Sci & Technol Korea, Daejeon, South Korea

[3] Chungnam Natl Univ, Dept Biol, Daejeon 34134, South Korea

来源：

BIOCHEMICAL PHARMACOLOGY | 2019年 / 163卷

基金：

新加坡国家研究基金会;

关键词：

Arp2/3; complex; ARPC2; Benproperine; Drug repurposing; Metastasis; ARP2/3; COMPLEX; ACTIN CYTOSKELETON; TARGET IDENTIFICATION; PROTEIN; DRUGS; DISSEMINATION; MOTILITY; INVASION;

D O I：

10.1016/j.bcp.2019.01.017

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：46 / 59

页数：14

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