Expression of p53 enhances selenite-induced superoxide production and apoptosis in human prostate cancer cells.
Although the anticancer effects of selenium have been shown in clinical, preclinical, and laboratory studies, the underlying mechanism(s) remains unclear. Our previous study showed that sodium selenite induced LNCaP human prostate cancer cell apoptosis in association with production of reactive oxygen species, alteration of cell redox state, and mitochondrial damage. In the present study, we showed that selenite-induced apoptosis was superoxide mediated and p53 dependent via mitochondrial pathways. In addition, we also showed that superoxide production by selenite was p53 dependent. Our study showed that wild-type p53-expressing LNCaP cells were more sensitive to selenite-induced apoptosis than p53-null PC3 cells. Selenite treatment resulted in high levels of superoxide production in LNCaP cells but only low levels in PC3 cells. LNCaP cells also showed sequential increases in levels of phosphorylated p53 (serine 15), total p53, Bax, and p21(Waf1) proteins following selenite treatment. The effects of selenite were suppressed by pretreatment with a synthetic superoxide dismutase mimic or by knockdown of p53 via RNA interference. LNCaP cells treated with selenite also showed p53 translocation to mitochondria, cytochrome c release into the cytosol, and activation of caspase-9. On the other hand, restoration of wild-type p53 expression in PC3 cells increased cellular sensitivity to selenite and resulted in increased superoxide production, caspase-9 activation, and apoptosis following selenite treatment. These results suggest that selenite induces apoptosis by producing superoxide to activate p53 and to induce p53 mitochondrial translocation. Activation of p53 in turn synergistically enhances superoxide production and apoptosis induced by selenite.
Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, Madison 53792, USA.
Rui
R
Zhao
Nong
N
Xiang
Frederick E
FE
Domann
Weixiong
W
Zhong
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D046188:Protein Modification, Translational; D018038:Sodium Selenite / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000172:deficiency / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494826:BAX protein, human; D008665:Metalloporphyrins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D013481:Superoxides; C050950:tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex; D018038:Sodium Selenite