Chronic nitric oxide exposure induces prostate cell carcinogenesis, involving genetic instability and a pro-tumorigenic secretory phenotype
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Prostate cancer is the second most commonly diagnosed cancer, and ranked third in the causes of death from cancer in Irish men. Inflammation has been implicated in prostate carcinogenesis, with the overexpression of NOS2 and concomitant nitric oxide (NO) release associated with cancer initiation and progression. The aim of this study was to characterise the effects of NO on normal prostate epithelial cells, and to determine whether prolonged exposure to NO could result in their malignant transformation. Results showed that NO induced the anchorage independent growth of normal prostate cells and the acquisition of several cancer-like characteristics. Short-term effects of NO included cellular growth inhibition involving a p53/p21 mediated cell cycle arrest, accompanied by the secretion of cytokines and growth factors. In addition, NO was shown to induce DNA damage in these cells, thereby fostering an environment of genomic instability. Prolonged exposure to NO resulted in the transformation of prostate epithelial cells, with alteration of their morphology from epithelial to mesenchymal-like, in conjunction with an increased migratory and invasive capacity. Moreover, long term exposure to NO led to decreased PTEN expression and increased phosphorylation of Akt, enabling sustained proliferation of the cells, and the ability to bypass p53/p21 arrest in serum free conditions. Prostate epithelial cells exposed to NO for prolonged periods displayed increased resistance to apoptosis, coupled with a dampened p53/p21 response to the DNA damaging agent etoposide. In addition, long term NO exposed cells secreted increased levels of IL-6 and IL-8 pro-tumourigenic cytokines. In summary, we have shown that long term exposure to NO selects for a population of cells with an impaired p53/p21 response, increased genomic instability and migratory/invasiveness, that are able to withstand nutrient deprivation and display increased survival in the face of chemotherapeutics.