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Pimozide suppresses cancer cell migration and tumor metastasis through binding to ARPC2, a subunit of the Arp2/3 complex
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Pimozide suppresses cancer cell migration and tumor metastasis through binding to ARPC2, a subunit of the Arp2/3 complex
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Journal Article
Pimozide suppresses cancer cell migration and tumor metastasis through binding to ARPC2, a subunit of the Arp2/3 complex
2019
Overview
ARPC2 is a subunit of the Arp2/3 complex, which is essential for lamellipodia, invadopodia and filopodia, and ARPC2 has been identified as a migrastatic target molecule. To identify ARPC2 inhibitors, we generated an ARPC2 knockout DLD‐1 human colon cancer cell line using the clustered regularly interspaced short palindromic repeats/CRISPR‐associated protein 9 (CRISPR/Cas9) system and explored gene signature‐based strategies, such as a connectivity map (CMap) using the gene expression profiling data of ARPC2 knockout and knockdown cells. From the CMap‐based drug discovery strategy, we identified pimozide (a clinically used antipsychotic drug) as a migrastatic drug and ARPC2 inhibitor. Pimozide inhibited the migration and invasion of various cancer cells. Through drug affinity responsive target stability (DARTS) analysis and cellular thermal shift assay (CETSA), it was confirmed that pimozide directly binds to ARPC2. Pimozide increased the lag phase of Arp2/3 complex‐dependent actin polymerization and inhibited the vinculin‐mediated recruitment of ARPC2 to focal adhesions in cancer cells. To validate the likely binding of pimozide to ARPC2, mutant cells, including ARPC2F225A, ARPC2F247A and ARPC2Y250F cells, were prepared using ARPC2 knockout cells prepared by gene‐editing technology. Pimozide strongly inhibited the migration of mutant cells because the mutated ARPC2 likely has a larger binding pocket than the wild‐type ARPC2. Therefore, pimozide is a potential ARPC2 inhibitor, and ARPC2 is a new molecular target. Taken together, the results of the present study provide new insights into the molecular mechanism and target that are responsible for the antitumor and antimetastatic activity of pimozide. Pimozide is identified as a migrastatic drug and ARPC2 inhibitor from connectivity map‐based drug discovery strategy. Pimozide inhibits migration and invasion in various cancer cell lines, and suppresses metastasis in an in vivo antimetastatic assay. Through drug affinity responsive target stability (DARTS) analysis and cellular thermal shift assay (CETSA), it was confirmed that pimozide directly binds to ARPC2.
Publisher
John Wiley & Sons, Inc,John Wiley and Sons Inc
Subject
/ Actin-Related Protein 2-3 Complex - antagonists & inhibitors
/ Actin-Related Protein 2-3 Complex - metabolism
/ actin‐related protein 2/3 complex
/ actin‐related protein 2/3 complex subunit 2
/ Animals
/ Antineoplastic Agents - pharmacology
/ Cell Movement - drug effects
/ CRISPR
/ Dopamine
/ Enzymes
/ Genomes
/ Humans
/ Mice
/ Neoplasm Metastasis - prevention & control
/ Original
/ pimozide
/ Proteins
/ R&D
/ Vinculin
