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

Yong Xu, Fang Fang, Daret K. St. Clair, Sajni Josson, Pradoldej Sompol, Ivan Spasojevic, William H. St. Clair

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Nuclear factor-κB 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 1α,25-dihydroxyvitamin D3 [1α,25-(OH) 2D3] with the vitamin D receptor significantly enhances radiosensitivity of prostate cancer cells at clinically relevant radiation doses. The radiosensitization effect of 1α,25-(OH)2D 3 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 1α,25-(OH)2D3 exerts its radiosensitization effect and that 1α,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.

Original languageEnglish
Pages (from-to)2048-2056
Number of pages9
JournalMolecular Cancer Therapeutics
Volume6
Issue number7
DOIs
StatePublished - Jul 1 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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