Author ORCID Identifier

https://orcid.org/0000-0002-6234-5034

Date Available

9-8-2023

Year of Publication

2023

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Toxicology and Cancer Biology

Advisor

Dr. Xiaoqi Liu

Abstract

Polo-like kinase 1 (PLK1) is a well- characterized regulator of cell division and is known to be highly expressed in certain types of tumors. It has been demonstrated the multifaceted roles of PLK1 in regulation of transcription, translation, epigenetics, DNA damage and cellular metabolism et al. Despite these findings, the precise mechanisms by which PLK1 regulates these processes beyond mitosis remain unclear. PLK1-mediated phosphorylation and misregulation of its substrates has been linked to tumorigenesis, cancer progression, drug resistance and worse prognosis. In this study, we investigated the non-canonical functions of PLK1 in cancer metabolism and drug resistance. We found that PLK1 phosphorylates pyruvate dehydrogenase subunit E1 alpha (PDHA1) at T57, resulting in the dissociation of the PDHA1/PDHB complex and inhibition of carbon influx into the TCA cycle. This ultimately leads to the repression of mitochondrial activity and reprogramming of metabolism in Cr(VI)-associated lung cancer progression. Furthermore, our study revealed that PLK1-mediated phosphorylation of programmed cell death 4 (PDCD4) at S239 induces its degradation, which in turn enhances resistance to enzalutamide treatment via activation of the c-MYC/GLIs/UGT2B15 axis in prostate cancer. Our study sheds light on the non-canonical roles of PLK1 in cancer metabolism and drug resistance, and provides new insights for improving therapeutic efficacy in cancer therapy.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2023.403

Funding Information

The research was generously supported by NIH R01 CA157429 (X. Liu) in 2020, R01 CA196634 (X. Liu) in 2018.

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