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Author ORCID Identifier

https://orcid.org/0000-0001-7005-9647

Date Available

5-1-2026

Year of Publication

2026

Document Type

Master's Thesis

Degree Name

Master of Science (MS)

College

Medicine

Department/School/Program

Toxicology and Cancer Biology

Faculty

Subbarao Bondada

Faculty

Yekaterina Zaytseva

Abstract

Prostate cancer progression and therapeutic resistance are closely linked to alterations in redox homeostasis and cell cycle regulation. Nuclear factor erythroid 2–related factor 2 (NRF2) is a master regulator of antioxidant responses, yet the mechanisms integrating cell cycle signaling with NRF2 activity in prostate cancer remain poorly defined. In this study, we identify polo‑like kinase 1 (PLK1) as a novel regulator of NRF2 through direct phosphorylation at serine 253 (S253). Using bioinformatic prediction, mass spectrometry, in vitro kinase assays, and cell‑based analyses, we demonstrate that PLK1 phosphorylates NRF2 at S253 in a cell cycle–dependent manner, with maximal phosphorylation during mitosis. Phosphorylation at this site enhances NRF2 protein stability, promotes nuclear accumulation, and increases transcriptional activity of antioxidant and cytoprotective target genes. Functional studies reveal that phosphorylation‑deficient NRF2 (S253A) results in elevated reactive oxygen species, impaired mitochondrial respiration, reduced proliferation, and diminished migration and invasion, whereas phospho‑mimetic NRF2 (S253D) promotes epithelial‑to‑mesenchymal transition, chemoresistance, and metabolic fitness. Importantly, immunohistochemical analysis of human prostate cancer specimens shows increased PLK1 expression and phospho‑NRF2 levels in advanced and castration‑resistant disease. Collectively, these findings uncover a previously unrecognized PLK1–NRF2 signaling axis that links mitotic control to redox regulation and prostate cancer aggressiveness, highlighting NRF2 S253 phosphorylation as a potential biomarker and therapeutic target in advanced prostate cancer.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2026.211

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Funding Information

This work was supported by National Institutes of Health grant R01CA256893, "Enhancing the efficacy of androgen signaling inhibitors in prostate cancer", to Dr. Xiaoqi Liu (University of Kentucky, 2025). 

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