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Inhibition of glycogen synthase kinase-3 beta induces apoptosis and mitotic
catastrophe by disrupting centrosome regulation in cancer cells
#MMPMID26292722
Yoshino Y
; Ishioka C
Sci Rep
2015[Aug]; 5
(?): 13249
PMID26292722
show ga
Glycogen synthase kinase-3 beta (GSK-3?) has been investigated as a therapeutic
target for numerous human diseases including cancer because of their diverse
cellular functions. Although GSK-3? inhibitors have been investigated as
anticancer reagents, precise biological mechanisms remain to be determined. In
this study, we investigated the anticancer effects of GSK-3? inhibitors on cancer
cell lines and observed centrosome dysregulation which resulted in abnormal
mitosis. Mitotic checkpoints sensed the mitotic abnormalities and induced
apoptosis. For cells that were inherently resistant to apoptosis, cell death
distinct from apoptosis was induced. After GSK-3? inhibitor treatment, these
cells exhibited characteristic features of mitotic catastrophe, including
distended and multivesiculated nuclei and inappropriate reductions in cyclin B1
expression. This suggested that mitotic catastrophe was an alternative mechanism
in cells resistant to apoptosis. Although the role of GSK-3? in centrosomes has
not yet been clarified, phosphorylated GSK-3? was localised in centrosomes. From
these data, GSK-3? seems to regulate centrosome function. Thus, we propose that
centrosome dysregulation is an important mechanism for the anticancer effects of
GSK-3? inhibitors and that mitotic catastrophe serves as a safe-guard system to
remove cells with any mitotic abnormalities induced by GSK-3? inhibition.
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