Inhibitors of the VEGF Receptor Suppress HeLa S3 Cell Proliferation via Misalignment of Chromosomes and Rotation of the Mitotic Spindle, Causing a Delay in M-Phase Progression

Cell division is the process by which replicated chromosomes are separated into two daughter cells. Although regulation of M phase has been extensively investigated, not all regulating factors have been identified. Over the course of our research, small molecules were screened to identify those that...

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Published in:International journal of molecular sciences 2018-12, Vol.19 (12), p.4014
Main Authors: Okumura, Daiki, Hagino, Mari, Yamagishi, Akane, Kaibori, Yuichiro, Munira, Sirajam, Saito, Youhei, Nakayama, Yuji
Format: Article
Language:English
Subjects:
A83-01
AKT protein
Angiogenesis
Apoptosis
Cancer
Caspase-3
Cell cycle
Cell division
Cell growth
Cell proliferation
Chromosomes
Delay
Growth factors
Immunofluorescence
Inhibitors
Ki8751
Kinases
M phase
Misalignment
Permeability
Phosphorylation
RO-3306
Rotation
spindle assembly checkpoint
spindle rotation
Spindles
SU4312
Synchronism
Synchronization
Vascular endothelial growth factor
Vascular endothelial growth factor receptors
VEGFR
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Summary:Cell division is the process by which replicated chromosomes are separated into two daughter cells. Although regulation of M phase has been extensively investigated, not all regulating factors have been identified. Over the course of our research, small molecules were screened to identify those that regulate M phase. In the present study, the vascular endothelial growth factor receptor (VEGFR) inhibitors A83-01, SU4312, and Ki8751 were examined to determine their effects on M phase. Treatment of HeLa S3 cells with these inhibitors suppressed cell proliferation in a concentration-dependent manner, and also suppressed Akt phosphorylation at Ser473, a marker of Akt activation. Interestingly, cleaved caspase-3 was detected in Adriamycin-treated cells but not in inhibitor-treated cells, suggesting that these inhibitors do not suppress cell proliferation by causing apoptosis. A cell cycle synchronization experiment showed that these inhibitors delayed M phase progression, whereas immunofluorescence staining and time-lapse imaging revealed that the M phase delay was accompanied by misalignment of chromosomes and rotation of the mitotic spindle. Treatment with the Mps1 inhibitor AZ3146 prevented the SU4312-induced M phase delay. In conclusion, the VEGFR inhibitors investigated here suppress cell proliferation by spindle assembly checkpoint-induced M phase delay, via misalignment of chromosomes and rotation of the mitotic spindle.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms19124014