Suppression of RelB-mediated manganese superoxide dismutase expression reveals a primary mechanism for radiosensitization effect of 1α,25-dihydroxyvitamin D3 in prostate cancer cells

Nuclear factor-kappa B provides an adaptive response to protect cancer cells against cytotoxicity induced by redox active therapeutics. ReIB is uniquely expressed at a high level in prostate cancer with high Gleason scores. Recently, we showed that the level of ROB rapidly increases in androgen-independent prostate cancer cells after exposure to ionizing radiation (111), leading to a reduction in intrinsic radiosensitivity. Here, we show that interaction of 1 alpha,25-dihydroxyvitamin D-3 [1 alpha,25-(OH)(2)D-3] with the vitamin D receptor significantly enhances radiosensitivity of prostate cancer cells at clinically relevant radiation doses. The radiosensitization effect of 1 alpha,25-(OH)(2)D-3 is mediated, at least in part, by selectively suppressing IR-mediated ROB activation, leading to a reduced expression of its target gene MnSOD, a primary antioxidant enzyme in mitochondria. These results suggest that suppression of manganese superoxide dismutase is a mechanism by which 1 alpha,25-(OH)(2)D-3 exerts its radio-sensitization effect and that 1 alpha,25-(OH)(2)D-3 may serve as an effective pharmacologic agent for selectively sensitizing prostate cancer cells to IR via suppression of antioxidant responses in mitochondria.