Suppression of RelB-mediated manganese superoxide dismutase expression reveals a primary mechanism for radiosensitization effect of 1alpha,25-dihydroxyvitamin D(3) in prostate cancer cells.
Nuclear factor-kappaB 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 1alpha,25-dihydroxyvitamin D(3) [1alpha,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 1alpha,25-(OH)(2)D(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 1alpha,25-(OH)(2)D(3) exerts its radiosensitization effect and that 1alpha,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.
Xu
Yong
Y
Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
Fang
Fang
F
St Clair
Daret K
DK
Josson
Sajni
S
Sompol
Pradoldej
P
Spasojevic
Ivan
I
St Clair
William H
WH
D000975:Antioxidants / Q000378:metabolism; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors*; D051841:Transcription Factor RelB / Q000378:metabolism*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
D000975:Antioxidants; C497593:RELB protein, human; D034741:RNA, Small Interfering; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D051841:Transcription Factor RelB; D013482:Superoxide Dismutase