ALK Inhibitors-Induced M Phase Delay Contributes to The Suppression of Cell Proliferation
| Autor: | Ryuzaburo Yuki, Youhei Saito, Sirajam Munira, Yuji Nakayama |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Mad2 lcsh:RC254-282 Article 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases misalignment medicine Anaplastic lymphoma kinase crizotinib Crizotinib Ceritinib Cell growth Chemistry SAC lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Spindle checkpoint 030104 developmental biology cell proliferation Oncology ALK 030220 oncology & carcinogenesis Cancer cell Cancer research M phase Tyrosine kinase medicine.drug RO-3306 |
| Zdroj: | Cancers, Vol 12, Iss 1054, p 1054 (2020) Cancers Volume 12 Issue 4 |
| ISSN: | 2072-6694 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|