Abstract
BackgroundHormone-resistant (HR) prostate cancers are highly aggressive and respond poorly to treatment. IL-6/STAT3 signaling has been identified to link with the transition of HR and aggressive tumor behavior. The role of IL-6 in the radiation response of prostate cancer was investigated in the present study.Material and methodsThe murine prostate cancer cell line (TRAMP-C1) and the hormone-resistant cell sub-line, TRAMP-HR, were used to assess the radiation response using in vitro clonogenic assays and tumor growth delay in vivo. Biological changes following irradiation were investigated by means of experimental manipulation of IL-6 signaling. Correlations among IL-6 levels, tumor regrowth, angiogenesis and myeloid-derived suppressor cell (MDSC) recruitment were examined in an animal model.ResultsHR prostate cancer cells had a higher expression of IL-6 and more activated STAT3, compared to TRAMP-C1 cells. HR prostate cancer cells had a greater capacity to scavenge reactive oxygen species, suffered less apoptosis, and subsequently were more likely to survive after irradiation. Moreover, IL-6 expression was positively linked to irradiation and radiation resistance. IL-6 inhibition enhanced the radiation sensitivity of prostate cancer, which was associated with increased p53, RT-induced ROS and oxidative DNA damage. Furthermore, when mice were irradiated with a sub-lethal dose, inhibition of IL-6 protein expression attenuated angiogenesis, MDSC recruitment, and decreased tumor regrowth.ConclusionThese data demonstrate that IL-6 is important in the biological sequelae following irradiation. Therefore, treatment with concurrent IL-6 inhibition is a potential therapeutic strategy for increasing the radiation response of prostate cancer.
Highlights
Radiation therapy (RT) is an important treatment modality for localized prostate cancer and leads to improved local control and disease-free survival of prostate cancer patients
HR prostate cancer cells had a greater capacity to scavenge reactive oxygen species, suffered less apoptosis, and subsequently were more likely to survive after irradiation
Response to radiation treatment Prostate cancer cells were exposed to single radiation doses of 0, 3, 6 or 9 Gy and their survival determined by colony formation assays
Summary
Radiation therapy (RT) is an important treatment modality for localized prostate cancer and leads to improved local control and disease-free survival of prostate cancer patients. We reported previously that overexpressed IL-6 and activated STAT3 signaling are critical for aggressive tumor behavior and the transition of HR prostate cancer [19,20]. We performed cell-culture and immunocompetent animal experiments to determine the correlation between IL-6 and the biological consequences following irradiation including tumor regrowth, angiogenesis and MDSC recruitment. This investigation of the role of IL-6 in prostate cancer might lead to new strategies of enhancing the radiation response of prostate cancer. Hormone-resistant (HR) prostate cancers are highly aggressive and respond poorly to treatment. The role of IL-6 in the radiation response of prostate cancer was investigated in the present study
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