RRC ID 71898
Author Sawada JI, Matsuno K, Ogo N, Asai A.
Title Various effects of two types of kinesin-5 inhibitors on mitosis and cell proliferation.
Journal Biochem Pharmacol
Abstract Kinesin-5 has received considerable attention as a new target for mitosis. Various small-molecule compounds targeting kinesin-5 have been developed in the last few decades. However, the differences in the cellular effects of kinesin-5 inhibitors remain poorly understood. Here, we used two different kinesin-5 inhibitors, biphenyl-type PVZB1194 and S-trityl-L-cysteine-type PVEI0021, to examine their effects on molecular events involving kinesin-5. Our biochemical study of kinesin-5 protein-protein interactions showed that PVZB1194-treated kinesin-5 interacted with TPX2 microtubule nucleation factor, Aurora-A kinase, receptor for hyaluronan-mediated motility, and γ-tubulin, as did untreated mitotic kinesin-5. However, PVEI0021 prevented kinesin-5 from binding to these proteins. In mitotic HeLa cells recovered from nocodazole inhibition, kinesin-5 colocalized with these binding proteins, along with microtubules nucleated near kinetochores. By acting on kinesin-5 interactions with chromatin-associated microtubules, PVZB1194, rather than PVEI0021, not only affected the formation of dispersed microtubule clusters but also enhanced the stability of microtubules. In addition, screening for mitotic inhibitors working synergistically with the kinesin-5 inhibitors revealed that paclitaxel synergistically inhibited HeLa cell proliferation only with PVZB1194. In contrast, the Aurora-A inhibitor MLN8237 exerted a synergistic anti-cell proliferation effect when combined with either inhibitor. Together, these results have provided a better understanding of the molecular action of kinesin-5 inhibitors and indicate their usefulness as molecular tools for the study of mitosis and the development of anticancer agents.
Volume 193
Pages 114789
Published 2021-11-1
DOI 10.1016/j.bcp.2021.114789
PII S0006-2952(21)00405-6
PMID 34582773
MeSH Antineoplastic Agents / pharmacology* Azepines / pharmacology Biphenyl Compounds / pharmacology* Cell Proliferation / drug effects HeLa Cells Humans Kinesins / antagonists & inhibitors* Molecular Structure Protein Kinase Inhibitors / pharmacology Pyrimidines / pharmacology Sulfonamides / pharmacology*
IF 4.96
Human and Animal Cells HeLa.S3(RCB0191)