Plk1 Inhibits DNA Damage Response Through Numb and its Implication for Cancer Therapy
The tumor suppressor p53 plays critical roles in cancer treatment by inducing growth arrest, apoptosis and senescence. Moreover, disruption of the p53 pathway is believed to be one of the major reasons for tumor chemo-resistance. Thus, p53 and its regulatory proteins become appealing targets for novel anticancer drug development as well as combinational treatments with existing chemotherapeutic drugs. Polo-like kinase 1(Plk1) is a serine/threonine kinase highly expressed in different human cancers. Importantly, previous studies have indicated that Plk1 serves as a negative regulator of p53. In this dissertation, I first proposed a promising therapeutic strategy by combing Plk1 inhibitor with metformin in prostate cancer models. I was able to demonstrate that Plk1 inhibition synergizes with metformin to induce apoptosis of tumor cells in a p53-dependent manner. To further explore the role of Plk1 in p53 pathway regulation, I identified adaptor protein Numb as a novel substrate of Plk1. Mechanistically, my data indicated that Numb phosphorylation by Plk1 leads to Numb proteasomal degradation and impaired Numb/p53/DNA damage response pathway as Numb was well-recognized as a positive regulator of p53 function and stability. Furthermore, I also found that cells expressing the unphosphorylated form of Numb showed better response to chemotherapeutic drugs. Overall, the work presented in this dissertation advances the knowledge of p53 regulation by Plk1 and sheds light on possible future strategies to improve the efficacy of p53-based cancer therapy.
Liu, Purdue University.
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