Research Articles: Therapeutics, Targets, and Development

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

^{1 1}Graduate Center for Toxicology and ²Department of Radiation Medicine, University of Kentucky, Lexington, Kentucky and ³Department of Medicine, Duke University Medical Center, Durham, North Carolina

^* To whom correspondence should be addressed. E-mail: stclair{at}uky.edu.

	Abstract

Nuclear factor-B provides an adaptive response to protect cancer cells against cytotoxicity induced by redox active therapeutics. RelB is uniquely expressed at a high level in prostate cancer with high Gleason scores. Recently, we showed that the level of RelB rapidly increases in androgen-independent prostate cancer cells after exposure to ionizing radiation (IR), leading to a reduction in intrinsic radiosensitivity. Here, we show that interaction of 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] with the vitamin D receptor significantly enhances radiosensitivity of prostate cancer cells at clinically relevant radiation doses. The radiosensitization effect of 1,25-(OH)₂D₃ is mediated, at least in part, by selectively suppressing IR-mediated RelB 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 1,25-(OH)₂D₃ exerts its radiosensitization effect and that 1,25-(OH)₂D₃ may serve as an effective pharmacologic agent for selectively sensitizing prostate cancer cells to IR via suppression of antioxidant responses in mitochondria. [Mol Cancer Ther 2007;6(7):2048-56]

Key Words: Vitamin D3, Radiosensitization, Prostate cancer, RelB, MnSOD