Loss of p21Cip1/CDKN1A renders cancer cells susceptible to Polo-like kinase 1 inhibition

The deregulation of Polo-like kinase 1 is inversely linked to the prognosis of patients with diverse human tumors. Targeting Polo-like kinase 1 has been widely considered as one of the most promising strategies for molec
The deregulation of Polo-like kinase 1 is inversely linked to the prognosis of patients with diverse human tumors. Targeting Polo-like kinase 1 has been widely considered as one of the most promising strategies for molecular anticancer therapy. While the preclinical results are encouraging, the clinical outcomes are rather less inspiring by showing limited anticancer activity. It is thus of importance to identify molecules and mechanisms responsible for the sensitivity of Polo-like kinase 1 inhibition. We have recently shown that p21Cip1/CDKN1A is involved in the regulation of mitosis and its loss prolongs the mitotic duration accompanied by defects in chromosome segregation and cytokinesis in various tumor cells. In the present study, we demonstrate that p21 affects the efficacy of Polo-like kinase 1 inhibitors, especially Poloxin, a specific inhibitor of the unique Polo-box domain. Intriguingly, upon treatment with Polo-like kinase 1 inhibitors, p21 is increased in the cytoplasm, associated with anti-apoptosis, DNA repair and cell survival. By contrast, deficiency of p21 renders tumor cells more susceptible to Polo-like kinase 1 inhibition by showing a pronounced mitotic arrest, DNA damage and apoptosis. Furthermore, long-term treatment with Plk1 inhibitors induced fiercely the senescent state of tumor cells with functional p21. We suggest that the p21 status may be a useful biomarker for predicting the efficacy of Plk1 inhibition.
…show moreshow less

Metadaten
Author:Nina-Naomi Kreis, Frank Louwen, Brigitte Zimmer, Juping Yuan
URN:urn:nbn:de:hebis:30:3-373658
URL:http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=2844
DOI:http://dx.doi.org/10.18632/oncotarget.2844
ISSN:1949-2553
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=25483104
Parent Title (English):Oncotarget
Publisher:Impact Journals LLC
Place of publication:[S.l.]
Document Type:Article
Language:English
Date of Publication (online):2014/12/02
Date of first Publication:2014/12/02
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2015/10/09
Tag:DNA damage; Plk1 inhibitors; apoptosis; p21; senescence
Volume:6
Issue:9
Pagenumber:16
First Page:6611
Last Page:6626
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:371445167
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0

$Rev: 11761 $