Journal
NITRIC OXIDE-BIOLOGY AND CHEMISTRY
Volume 127, Issue -, Pages 44-53Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.niox.2022.07.005
Keywords
Prostate cancer; Nitric oxide; Invasive potential; Cellular transformation
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Funding
- Galway University Foundation [RNR1008]
- Science Foundation Ireland (SFI) [17/CDA/4638]
- European Regional Development Fund (ERDF) [13/RC/2073]
- Science Foundation Ireland (SFI) [17/CDA/4638] Funding Source: Science Foundation Ireland (SFI)
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NO plays a key role in the development and metastasis of prostate cancer, leading to DNA damage, cell migration, and increased resistance to chemotherapy.
Prostate cancer is a leading cause of cancer death in men. Inflammation and overexpression of inducible nitric oxide synthase (NOS2) have been implicated in prostate carcinogenesis. We aimed to explore the hypothesis that nitric oxide NO exerts pro-tumorigenic effects on prostate cells at physiologically relevant levels contributing to carcinogenesis. We investigated the impact of acute exposure of normal immortalised prostate cells (RWPE-1) to NO on cell proliferation and activation of DNA damage repair pathways. Furthermore we investigated the long term effects of chronic NO exposure on RWPE-1 cell migration and invasion potential and hallmarks of trans-formation. Our results demonstrate that NO induces DNA damage as indicated by gamma H2AX foci and p53 activation resulting in a G1/S phase block and activation of 53BP1 DNA damage repair protein. Long term adaption to NO results in increased migration and invasion potential, acquisition of anchorage independent growth and increased resistance to chemotherapy. This was recapitulated in PC3 and DU145 prostate cancer cells which upon chronic exposure to NO displayed increased cell migration, colony formation and increased resistance to chemotherapeutics. These findings indicate that NO may play a key role in the development of prostate cancer and the acquisition of an aggressive metastatic phenotype.
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