Abstract
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 IC50 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 IC50 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.
Highlights
Human anaplastic lymphoma kinase (ALK) is a receptor-type tyrosine kinase (RTK) composed of 1620 amino acids and belongs to the insulin receptor superfamily
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
One target of crizotinib is ALK tyrosine kinase, the expression of which depends on cell type
Summary
Human anaplastic lymphoma kinase (ALK) is a receptor-type tyrosine kinase (RTK) composed of 1620 amino acids and belongs to the insulin receptor superfamily. The expression of ALK is especially high in neonates and is found in discrete areas of the developing central and peripheral nervous systems [1]. ALK expression is reported in the adult mammalian hippocampus [2]. Consistent with this expression profile, ALK is reported to play a regulatory role in the function of the nervous system and in mammalian behavior [3]. Some proteins have been reported as ligands of ALK, including pleiotrophin, midkine, augmentor-β, and augmentor-α [4,5,6]. Like other RTKs, ALK is activated through autophosphorylation after ligand binding and receptor dimerization. The direct biological roles of ALK are not completely understood [7]
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