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.