Oncotarget

Reviews:

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

Frank Louwen and Juping Yuan _

PDF  |  HTML  |  How to cite  |  Order a Reprint

Oncotarget. 2013; 4:958-971. https://doi.org/10.18632/oncotarget.1096

Metrics: PDF 1591 views  |   HTML 2822 views  |   ?  


Abstract

Frank Louwen1 and Juping Yuan1

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

Correspondence:

Juping Yuan, email:

Keywords: Oncotargets

Received: June 13, 2013 Accepted: July 11, 2013 Published: July 13, 2013

Abstract

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 1096