The protein kinase Polo-like kinase-1 (PLK1) is an essential driver of mitosis and is oncogenic when expressed at elevated levels. Therefore, a number of inhibitors of PLK1 have been developed as potential anti-cancer therapeutic agents. While these inhibitors undergo clinical evaluation there has been evidence to show that they are less effective in killing cancer cells expressing the transcription factor p53. Normally, p53 is a potent tumour suppressor that has a classical role in orchestrating inhibition of cancer cell growth. However, under some circumstances p53 appears to protect cancer cells, due to cells undergoing a reversible growth arrest. This may allow cells to recover post-treatment. Here, it has been shown that a proportion of p53 competent cells treated with PLK1 inhibitors undergo a G1/S arrest. This is mediated by p53 and may offer protection to these cells. Application of PLK1 inhibitors also gives rise to DNA damage, induces p53, promotes increased p53 phosphorylation, and causes activation of downstream targets, such as p21. Inhibiting the DNA damage-activated protein kinases ATM and ATR prior to treatment with PLK1 inhibitors alleviates the activation of p53. Interestingly, the resulting duration of mitotic arrest from inhibition of PLK1 is markedly shorter in cells that are p53 competent. Study of the centrosomes after PLK1 inhibition highlighted that centrosome separation is more greatly impaired in cells deficient of p53. Furthermore, use of an inhibitor of Eg5, a motor protein involved in centrosome separation, resulted in similar phenotypes to that observed with inhibitors of PLK1. This suggests p53 has a potentially novel role in centrosome separation and has highly important implications for treatment with PLK1, and perhaps Eg5, inhibitors. This work suggests that screening of individual patients for the p53 status of their cancer could be a major consideration in prescribing use of these inhibitors.
|Date of Award||2017|
|Sponsors||Medical Research Council|
|Supervisor||David Meek (Supervisor) & Frances Fuller-Pace (Supervisor)|