Battle of the eternal rivals : restoring functional p53 and inhibiting Polo-like kinase 1 as cancer therapy

  • Polo-like kinase 1, a pivotal regulator of mitosis and cytokinesis, is highly expressed in a broad spectrum of tumors and its expression correlates often with poor prognosis, suggesting its potential as a therapeutic target. p53, the guardian of the genome, is the most important tumor suppressor. In this review, we address the intertwined relationship of these two key molecules by fighting each other as eternal rivals in many signaling pathways. p53 represses the promoter of Polo-like kinase 1, whereas Polo-like kinase 1 inhibits p53 and its family members p63 and p73 in cancer cells lacking functional p53. Plk1 inhibitors target all rapidly dividing cells irrespective of tumor cells or non-transformed normal but proliferating cells. Upon treatment with Plk1 inhibitors, p53 in tumor cells is activated and induces strong apoptosis, whereas tumor cells with inactive p53 arrest in mitosis with DNA damage. Thus, inactive p53 is not associated with a susceptible cytotoxicity of Polo-like kinase 1 inhibition and could rather foster the induction of polyploidy/aneuploidy in surviving cells. In addition, compared to the mono-treatment, combination of Polo-like kinase 1 inhibition with anti-mitotic or DNA damaging agents boosts more severe mitotic defects, effectually triggers apoptosis and strongly inhibits proliferation of cancer cells with functional p53. In this regard, restoration of p53 in tumor cells with loss or mutation of p53 will reinforce the cytotoxicity of combined Polo-like kinase 1 therapy and provide a proficient strategy for combating relapse and metastasis of cancer.

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Metadaten
Author:Frank LouwenGND, Juping YuanORCiDGND
URN:urn:nbn:de:hebis:30:3-325953
DOI:https://doi.org/10.18632/oncotarget.1096
ISSN:1949-2553
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/23948487
Parent Title (English):Oncotarget
Publisher:Impact Journals LLC
Place of publication:[S.l.]
Document Type:Article
Language:English
Date of Publication (online):2013/07/13
Date of first Publication:2013/07/13
Publishing Institution:Universit├Ątsbibliothek Johann Christian Senckenberg
Release Date:2014/05/23
Tag:Oncotargets
Volume:4
Issue:7
Page Number:14
First Page:958
Last Page:971
Note:
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
HeBIS-PPN:365060844
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universit├Ątspublikationen
Sammlung Biologie / Sondersammelgebiets-Volltexte
Licence (German):License LogoCreative Commons - Namensnennung 3.0