Exploration of inflammatory modulators nitric oxide and HERV-K in prostate cancer progression and diagnosis reveals a role for nitric oxide regulation of STAT3
McAuliffe, Jake
McAuliffe, Jake
Loading...
Repository DOI
Publication Date
2024-07-25
Type
doctoral thesis
Downloads
Citation
Abstract
Prostate cancer (PCa) remains a highly prevalent cancer worldwide, with approximately 500 yearly deaths attributed to it in Ireland. Inflammation bears responsibility for the emergence of several prostatic conditions, including PCa. NOS2 is a powerful and prolonged producer of nitric oxide (NO), which can be activated by inflammation, and has been implicated in prostate carcinogenesis and lethality. Chronic NO exposure has been shown to induce malignant transformation in normal prostate cells. This study aimed to explore whether long-term, chronic NO exposure would similarly confer PCa cell lines with increased aggressiveness. Results showed that chronic NO exposure conferred PCa cell lines with increased rates of proliferation, migration, and invasion. These chronically exposed cells also displayed increased chemoresistance, upregulated transcription of various pro-tumorigenic genes, and increased total STAT3 protein. STAT3, a master transcription factor, mediates several processes of cancer and has been associated with PCa. The relationship between STAT3 and NO is unclear, and this study further aimed to explore any relationship NO and its chronic exposure may have on STAT3 activity in PCa. Results indicated that NO can indeed phosphorylate STAT3 in PCa cells. Further, it was found that STAT3 inhibitors Niclosamide and STATTIC impede several Epithelial-to-Mesenchymal Transition (EMT) behaviours in PCa cells. Following chronic NO exposure, PCa cells were more sensitive to Niclosamide. The combination of DETA/NO and STAT3 inhibitors yielded a powerful additive cytotoxic effect. Inflammation and PCa have also been linked to Human Endogenous Retrovirus-K (HERV-K), an ancient viral integration to the genome which is largely silenced in somatic tissue. Elevated HERV-K(HML2) gag mRNA expression in PBMCs has previously been associated with PCa diagnosis. This study aimed to corroborate those findings and expand whether HERV-K(HML2) mRNA may contribute to improved PSA accuracy in diagnosing PCa and discern between Benign Prostatic Hyperplasia (BPH) and PCa. In the patient cohort, HERV-K gag and env2 mRNA was significantly elevated in PCa patients compared to BPH. In summary, this study has shown that chronic NO exposure induces increased aggressive behaviour in PCa cells, while also exposing a potential therapeutic opportunity via STAT3 inhibition, and thereby connecting NO and STAT3 in PCa. We also further argued the potential of HERV-K(HML2) as a potential biomarker for PCa diagnosis.
Funder
Publisher
University of Galway
Publisher DOI
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International