Targeting PAK1 with the Small Molecule Drug AK963/40708899 Suppresses Gastric Cancer Cell Proliferation and Invasion by Downregulation of PAK1 Activity and PAK1‐Related Signaling Pathways

ABSTRACT PAK1 (p21‐activated kinase 1) is a serine/threonine protein kinase which has been initially identified as downstream effector of the Rho GTPase family. In previous research, PAK1 has been involved in the regulation of diverse cellular processes, such as cell motility, cell proliferation, ge...

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Published in:Anatomical record (Hoboken, N.J. : 2007) N.J. : 2007), 2019-09, Vol.302 (9), p.1571-1579
Main Authors: Zhou, Ying, Zhang, Jian, Wang, Jian, Cheng, Mao‐Sheng, Zhao, Dong‐Mei, Li, Feng
Format: Article
Language:English
Subjects:
AK963/40708899
Cell activation
Cell adhesion
Cell adhesion & migration
Cell growth
Cell proliferation
Cofilin
Cytoskeleton
Extracellular signal-regulated kinase
Filopodia
Gastric cancer
Gene rearrangement
GTP-binding protein
Guanosine triphosphatases
inhibitor
Invasiveness
Kinases
PAK1
Protein kinase
Protein-serine/threonine kinase
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Summary:ABSTRACT PAK1 (p21‐activated kinase 1) is a serine/threonine protein kinase which has been initially identified as downstream effector of the Rho GTPase family. In previous research, PAK1 has been involved in the regulation of diverse cellular processes, such as cell motility, cell proliferation, gene transcription, cytoskeletal rearrangement, and cell invasion. Hyper‐activation of PAK1 was constantly observed in a variety of human cancer which make it a potential target of novel anti‐tumor drugs. To date, a great number of attentions focus on identifying the PAK1 inhibitors in medical and pharmaceutical fields. In this article, we found that a novel and potent PAK1 inhibitor, AK963/40708899, suppressed the proliferation of human gastric cancer cells significantly by downregulation of PAK1–NF‐κB–cyclinB1 pathway. In addition, AK963/40708899 inhibited the formation of filopodia and promoted cell adhesion which in turn inhibited invasive potential of gastric cells by negatively regulating PAK1–LIMKl–cofilin and PAK1–ERK–FAK pathways. Considering our result, AK963/40708899 would be a possible candidate for PAK1 targeted anti‐tumor drug. Anat Rec, 302:1571–1579, 2019. © 2019 American Association for Anatomy
ISSN:1932-8486
1932-8494
DOI:10.1002/ar.24095