Author ORCID Identifier
https://orcid.org/0000-0002-8869-8292
Date Available
8-2-2027
Year of Publication
2025
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Medicine
Department/School/Program
Toxicology and Cancer Biology
Faculty
Xiaoqi Liu
Faculty
Isabel Mellon
Abstract
Prostate cancer (PCa) remains one of the most prevalent malignancies and a leading cause of cancer-related death among men worldwide. Standard treatments targeting the androgen receptor (AR) pathway, including the second-generation AR inhibitor enzalutamide (ENZ), are initially effective in patients with castration-resistant prostate cancer (CRPC). However, resistance to ENZ frequently emerges, limiting its long-term efficacy. To address this challenge, we performed an FDA-approved drug screen. We identified artesunate (ART)—a semi-synthetic derivative of artemisinin and an anti-malarial agent—as a promising candidate to overcome ENZ resistance. Mechanistically, ART promotes the degradation of c-Myc, a transcription factor implicated in drug resistance, thereby restoring sensitivity to ENZ. Analysis of patient datasets further confirmed the clinical relevance of c-Myc in ENZ resistance. These findings support the potential repurposing of ART as part of a novel therapeutic strategy for ENZ-resistant prostate cancer.
In addition, we investigated the role of Polo-like kinase 1 (PLK1), a serine/threonine kinase and key regulator of cell division, in inflammation-associated colon cancer. Although PLK1 is typically overexpressed in tumors and associated with oncogenic processes, its function in the colon, particularly in the context of inflammation, remains unclear. Using both human IBD samples and DSS-treated mice, we observed elevated PLK1 expression in inflamed colonic tissues. In the AOM/DSS mouse model of colitis-associated colon cancer, we found that reduced PLK1 expression exacerbated inflammation and increased tumor burden, indicating a protective role. Further analysis revealed that PLK1 negatively regulates neutrophil infiltration and modulates key pathways involved in intestinal stem cell proliferation and differentiation. These results demonstrate a non-canonical, anti-inflammatory function of PLK1 in suppressing colitis-driven tumorigenesis.
Together, this body of work highlights two complementary therapeutic strategies: repurposing ART to enhance prostate cancer treatment and the role of PLK1 to mitigate inflammation-associated colon cancer. These findings offer new insights into overcoming drug resistance and controlling inflammation-driven tumorigenesis.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2025.276
Funding Information
National Cancer Institute [R01 CA256893, R01 CA264652, R01 CA157429, R01 CA272483, P30 CA177558, R01CA266579]
Recommended Citation
Wang, Xinyi, "EXPLORING NOVEL THERAPEUTIC STRATEGIES: DRUG REPURPOSING IN PROSTATE CANCER AND KINASE REGULATION IN INFLAMMATION-ASSOCIATED COLON CANCER" (2025). Theses and Dissertations--Toxicology and Cancer Biology. 65.
https://uknowledge.uky.edu/toxicology_etds/65
