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Cell Cycle. 2013 May 1;12(9):1340-51. doi: 10.4161/cc.24573. Epub 2013 Apr 10.

Polo-like kinase 1 inhibitors, mitotic stress and the tumor suppressor p53.

Author information

1
Department of Gynecology and Obstetrics, School of Medicine, J.W. Goethe-University, Frankfurt, Germany.

Abstract

Polo-like kinase 1 has been established as one of the most attractive targets for molecular cancer therapy. In fact, multiple small-molecule inhibitors targeting this kinase have been developed and intensively investigated. Recently, it has been reported that the cytotoxicity induced by Plk1 inhibition is elevated in cancer cells with inactive p53, leading to the hypothesis that inactive p53 is a predictive marker for the response of Plk1 inhibition. In our previous study based on different cancer cell lines, we showed that cancer cells with wild type p53 were more sensitive to Plk1 inhibition by inducing more apoptosis, compared with cancer cells depleted of p53. In the present work, we further demonstrate that in the presence of mitotic stress induced by different agents, Plk1 inhibitors strongly induced apoptosis in HCT116 p53(+/+) cells, whereas HCT116 p53(-/-) cells arrested in mitosis with less apoptosis. Depletion of p53 in HCT116 p53(+/+) or U2OS cells reduced the induction of apoptosis. Moreover, the surviving HCT116 p53(-/-) cells showed DNA damage and a strong capability of colony formation. Plk1 inhibition in combination with other anti-mitotic agents inhibited proliferation of tumor cells more strongly than Plk1 inhibition alone. Taken together, the data underscore that functional p53 strengthens the efficacy of Plk1 inhibition alone or in combination by strongly activating cell death signaling pathways. Further studies are required to investigate if the long-term outcomes of losing p53, such as low differential grade of tumor cells or defective DNA damage checkpoint, are responsible for the cytotoxicity of Plk1 inhibition.

KEYWORDS:

BI 2536; BI 6727; Poloxin; monastrol; p53

PMID:
23574746
PMCID:
PMC3674062
DOI:
10.4161/cc.24573
[Indexed for MEDLINE]
Free PMC Article

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