ALK Inhibitors-Induced M Phase Delay Contributes to the Suppression of Cell Proliferation

Anaplastic lymphoma kinase (ALK), a receptor-type tyrosine kinase, is involved in the pathogenesis of several cancers. ALK has been targeted with small molecule inhibitors for the treatment of different cancers, but absolute success remains elusive. In the present study, the effects of ALK inhibitor...

Full description

Saved in:
Bibliographic Details
Published in:Cancers 2020-04, Vol.12 (4), p.1054
Main Authors: Munira, Sirajam, Yuki, Ryuzaburo, Saito, Youhei, Nakayama, Yuji
Format: Article
Language:English
Subjects:
Anaphase
Cell fusion
Cell growth
Cell proliferation
Chromosomes
Kinases
Lung carcinoma
Mutation
Protein-tyrosine kinase
Spindles
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Anaplastic lymphoma kinase (ALK), a receptor-type tyrosine kinase, is involved in the pathogenesis of several cancers. ALK has been targeted with small molecule inhibitors for the treatment of different cancers, but absolute success remains elusive. In the present study, the effects of ALK inhibitors on M phase progression were evaluated. Crizotinib, ceritinib, and TAE684 suppressed proliferation of neuroblastoma SH-SY5Y cells in a concentration-dependent manner. At approximate IC concentrations, these inhibitors caused misorientation of spindles, misalignment of chromosomes and reduction in autophosphorylation. Similarly, knockdown of ALK caused M phase delay, which was rescued by re-expression of ALK. Time-lapse imaging revealed that anaphase onset was delayed. The monopolar spindle 1 (MPS1) inhibitor, AZ3146, and MAD2 knockdown led to a release from inhibitor-induced M phase delay, suggesting that spindle assembly checkpoint may be activated in ALK-inhibited cells. H2228 human lung carcinoma cells that express EML4-ALK fusion showed M phase delay in the presence of TAE684 at about IC concentrations. These results suggest that ALK plays a role in M phase regulation and ALK inhibition may contribute to the suppression of cell proliferation in ALK-expressing cancer cells.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers12041054