Oncotarget

Research Papers:

Combinatorial inhibition of Plk1 and PKCβ in cancer cells with different p53 status

Lisa Lange, Sarah Keppner-Witter, Juline Grigat and Birgit Spänkuch _

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Oncotarget. 2014; 5:2263-2275. https://doi.org/10.18632/oncotarget.1897

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Abstract

Lisa Lange1,*, Sarah Keppner-Witter2,*, Juline Grigat3, Birgit Spänkuch1

1 Friedrich-Schiller-University, CMB, Institute for Biochemistry, Hans-Knöll-Straße 2, 07745 Jena, Germany

2 Eberhard-Karls-University, Department of Gynecology, Calwer Straße 7, 72076 Tübingen, Germany

3 Department of Obstetrics and Gynecology, Medical School, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany

* These authors contributed equally

Correspondence:

Birgit Spänkuch, email:

Keywords: polo-like kinase 1, protein-kinase C β, Enzastaurin, SBE13, cell cycle

Received: March 11, 2014 Accepted: April 11, 2014 Published: April 12, 2014

Abstract

PKCβ and Plk1 are fascinating targets in cancer therapy. Therefore, we combined Enzastaurin targeting PKCβ and SBE13 targeting Plk1 to test synergistic effects in cells with different p53 status. We analyzed cell proliferation and apoptosis induction, and did Western blot and FACScan analyses to examine the combined PKCβ and Plk1 inhibition. p53-wild-type cells are more resistant to the combinatorial treatment than p53-deficient cells, which displayed a synergistic reduction of cell proliferation after the combination. HeLa, MCF-7 and HCT116p53wt and HCT116p53-/- cells differed in their cell cycle distribution after combinatorial treatment in dependence on a functional p53-dependent G1/S checkpoint (p53-deficient cells showed an enrichment in S and G2/M, p53-wild-type cells in G0/G1 phase). hTERT-RPE1 cells did not show the synergistic effects of cancer cells.

Thus, we demonstrate for the first time that Plk1 inhibition using SBE13 enhances the effects of Enzastaurin in cancer cells. HCT116p53wt and HCT116p53-/- cells confirmed the p53-dependence of different effects after Plk1 and PKCβ inhibition observed in HeLa and MCF-7 cells. Obviously, p53 protects cells from the cytotoxicity of Enzastaurin in combination with SBE13. For that reason this combination can be useful to treat p53-deficient cancers, without displaying toxicity to normal cells, which all have functional p53.


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