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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.
Highlights
Polo-like kinase 1 and the tumor suppressor p53Since the discovery of Polo kinase in Drosophila in 1988 [1], the Polo-like kinase (Plk) family has been attracting enormous attention, both in academia and in pharmaceutical industry
Five members of the Plk family have been discovered in humans and these serine/threonine kinases have emerged as key players by performing crucial functions in the cell cycle, DNA damage response and neuron biology [2,3,4,5,6]
We have examined the cytotoxicity of Plk1 inhibitors/depletion in various cancer cell lines with or without functional p53 [126]
Summary
Since the discovery of Polo kinase in Drosophila in 1988 [1], the Polo-like kinase (Plk) family has been attracting enormous attention, both in academia and in pharmaceutical industry. Under severe mitotic stress induced by combined therapy, HCT116 p53+/+ cells conduct apoptosis in mitosis or exit mitosis into the G1 tetraploidy followed by p53-dependent apoptosis, whereas HCT116 p53-/cells arrest in mitosis, possibly to initiate another round of DNA replication as suggested [142,143] In this regard, Plk inhibition in cancer cells with inactive p53 could lead to an accumulation of polyploidy/aneuploidy, due to the lack of p53-mediated cell death signaling pathway. These data are in consistence with our data that the combination of Plk inhibition with anti-mitotic or DNA damaging agents triggers more apoptosis and inhibits more strongly proliferation of cancer cells compared to the mono-treatment [102,141,148,149] Both Plk inhibitors and microtubule-inhibitory agents prolong mitotic arrest, promoting p53 stabilization, Bax expression, caspase activation and apoptosis induction [126,150,151,152]. We will reach the goal of cancer therapy that “the wolves are sated, and the sheep are intact” [154,155]
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