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Inhibition of glycogen synthase kinase-3 beta induces apoptosis and mitotic catastrophe by disrupting centrosome regulation in cancer cells.

Yoshino Y, Ishioka C - Sci Rep (2015)

Bottom Line: After GSK-3β inhibitor treatment, these cells exhibited characteristic features of mitotic catastrophe, including distended and multivesiculated nuclei and inappropriate reductions in cyclin B1 expression.From these data, GSK-3β seems to regulate centrosome function.Thus, we propose that centrosome dysregulation is an important mechanism for the anticancer effects of GSK-3β inhibitors and that mitotic catastrophe serves as a safe-guard system to remove cells with any mitotic abnormalities induced by GSK-3β inhibition.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo-machi 4-1, Aoba-ku, Sendai 980-8575, Japan.

ABSTRACT
Glycogen synthase kinase-3 beta (GSK-3β) has been investigated as a therapeutic target for numerous human diseases including cancer because of their diverse cellular functions. Although GSK-3β inhibitors have been investigated as anticancer reagents, precise biological mechanisms remain to be determined. In this study, we investigated the anticancer effects of GSK-3β 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-3β 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-3β in centrosomes has not yet been clarified, phosphorylated GSK-3β was localised in centrosomes. From these data, GSK-3β seems to regulate centrosome function. Thus, we propose that centrosome dysregulation is an important mechanism for the anticancer effects of GSK-3β inhibitors and that mitotic catastrophe serves as a safe-guard system to remove cells with any mitotic abnormalities induced by GSK-3β inhibition.

No MeSH data available.


Related in: MedlinePlus

AR-A014418 antiproliferative effects.(a) Representative data for AR-A014418 growth inhibitory effects on eight cancer cell lines. Cell counts were determined after cells were exposed to AR-A014418 at indicated concentrations for 120 h. Cell growth relative to the control (DMSO) was determined. (b) IC50 values of cell lines at 120 h after adding AR-A014418. IC50 values were determined from at least three independent experiments using a logistic regression model. Error bars indicate 95% confidence intervals (CIs) (*>30 μM).
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f1: AR-A014418 antiproliferative effects.(a) Representative data for AR-A014418 growth inhibitory effects on eight cancer cell lines. Cell counts were determined after cells were exposed to AR-A014418 at indicated concentrations for 120 h. Cell growth relative to the control (DMSO) was determined. (b) IC50 values of cell lines at 120 h after adding AR-A014418. IC50 values were determined from at least three independent experiments using a logistic regression model. Error bars indicate 95% confidence intervals (CIs) (*>30 μM).

Mentions: To investigate the inhibitory effects of a GSK-3β inhibitor on cancer cell proliferation, cell proliferation was determined after long-term (120 h) treatment with AR-A014418, a specific GSK-3β inhibitor17 (Fig. 1a). IC50 values were determined using a logistic regression analysis from at least three independent experiments (Fig. 1b). Based on their IC50 values, we selected five cell lines for following study: HCT 116, MDA-MB-435S; and RKO as sensitive cell lines, and KPK13 and SUIT-2 as relatively insensitive cell lines. Shorter treatment (72 h) with AR-A0114418 did not show significant growth suppression below 20 μM (data not shown).


Inhibition of glycogen synthase kinase-3 beta induces apoptosis and mitotic catastrophe by disrupting centrosome regulation in cancer cells.

Yoshino Y, Ishioka C - Sci Rep (2015)

AR-A014418 antiproliferative effects.(a) Representative data for AR-A014418 growth inhibitory effects on eight cancer cell lines. Cell counts were determined after cells were exposed to AR-A014418 at indicated concentrations for 120 h. Cell growth relative to the control (DMSO) was determined. (b) IC50 values of cell lines at 120 h after adding AR-A014418. IC50 values were determined from at least three independent experiments using a logistic regression model. Error bars indicate 95% confidence intervals (CIs) (*>30 μM).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543981&req=5

f1: AR-A014418 antiproliferative effects.(a) Representative data for AR-A014418 growth inhibitory effects on eight cancer cell lines. Cell counts were determined after cells were exposed to AR-A014418 at indicated concentrations for 120 h. Cell growth relative to the control (DMSO) was determined. (b) IC50 values of cell lines at 120 h after adding AR-A014418. IC50 values were determined from at least three independent experiments using a logistic regression model. Error bars indicate 95% confidence intervals (CIs) (*>30 μM).
Mentions: To investigate the inhibitory effects of a GSK-3β inhibitor on cancer cell proliferation, cell proliferation was determined after long-term (120 h) treatment with AR-A014418, a specific GSK-3β inhibitor17 (Fig. 1a). IC50 values were determined using a logistic regression analysis from at least three independent experiments (Fig. 1b). Based on their IC50 values, we selected five cell lines for following study: HCT 116, MDA-MB-435S; and RKO as sensitive cell lines, and KPK13 and SUIT-2 as relatively insensitive cell lines. Shorter treatment (72 h) with AR-A0114418 did not show significant growth suppression below 20 μM (data not shown).

Bottom Line: After GSK-3β inhibitor treatment, these cells exhibited characteristic features of mitotic catastrophe, including distended and multivesiculated nuclei and inappropriate reductions in cyclin B1 expression.From these data, GSK-3β seems to regulate centrosome function.Thus, we propose that centrosome dysregulation is an important mechanism for the anticancer effects of GSK-3β inhibitors and that mitotic catastrophe serves as a safe-guard system to remove cells with any mitotic abnormalities induced by GSK-3β inhibition.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo-machi 4-1, Aoba-ku, Sendai 980-8575, Japan.

ABSTRACT
Glycogen synthase kinase-3 beta (GSK-3β) has been investigated as a therapeutic target for numerous human diseases including cancer because of their diverse cellular functions. Although GSK-3β inhibitors have been investigated as anticancer reagents, precise biological mechanisms remain to be determined. In this study, we investigated the anticancer effects of GSK-3β 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-3β 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-3β in centrosomes has not yet been clarified, phosphorylated GSK-3β was localised in centrosomes. From these data, GSK-3β seems to regulate centrosome function. Thus, we propose that centrosome dysregulation is an important mechanism for the anticancer effects of GSK-3β inhibitors and that mitotic catastrophe serves as a safe-guard system to remove cells with any mitotic abnormalities induced by GSK-3β inhibition.

No MeSH data available.


Related in: MedlinePlus