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Research Articles

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

Requests for reprints: William H. St. Clair, Department of Radiation Medicine, University of Kentucky College of Medicine, Lexington, KY 40536. Phone: 859-323-6486; Fax: 859-257-4931. 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]

Grant support: University of Kentucky Research Foundation and NIH grant CA 49797.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/13/06; revised 4/21/07; accepted 5/15/07.