Selenium compounds inhibit I kappa B kinase (IKK) and nuclear factor-kappa B (NF-kappa B) in prostate cancer cells.
Selenium compounds are potential chemopreventive agents for prostate cancer. There are several proposed mechanisms for their anticancer effect, including enhanced apoptosis of transformed cells. Because the transcription factor nuclear factor-kappa B (NF-kappa B) is often constitutively activated in tumors and is a key antiapoptotic factor in mammalian cells, we tested whether selenium inhibited NF-kappa B activity in prostate cancer cells. In our work, we used sodium selenite and a novel synthetic compound, methylseleninic acid (MSeA), that served as a precursor of the putative active monomethyl metabolite methylselenol. We found that both selenium forms inhibited cell growth and induced apoptosis in DU145 and JCA1 prostate carcinoma cells. Sodium selenite and MeSeA, at the concentrations that induced apoptosis, inhibited NF-kappa B DNA binding induced by tumor necrosis factor-alpha and lipopolysaccharide in DU145 and JCA1 prostate cells. Both compounds also inhibited kappa B. Luciferase reporter activity in prostate cells. A key to NF-kappa B regulation is the inhibitory kappa B (I kappa B) proteins that in response to diverse stimuli are rapidly phosphorylated by I kappa B kinase complex, ubiquitinated, and undergo degradation, releasing NF-kappa B factor. We showed that sodium selenite and MSeA inhibited I kappa B kinase activation and I kappa B-alpha phosphorylation and degradation induced by TNF-alpha and lipopolysaccharide in prostate cells. NF-kappa B blockage by I kappa B-alpha d.n. mutant resulted in the sensitization of prostate carcinoma cells to apoptosis induced by selenium compounds. These results suggest that selenium may target the NF-kappa B activation pathway to exert, at least in part, its cancer chemopreventive effect in prostate.
Gasparian
Alexander V
AV
AMC Cancer Research Center, 1600 Pierce Street, Denver, CO 80214, USA.
Yao
Ya Juan
YJ
Lü
Junxuan
J
Yemelyanov
Alexander Y
AY
Lyakh
Lyudmila A
LA
Slaga
Thomas J
TJ
Budunova
Irina V
IV
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000256:Adenoviridae / Q000235:genetics; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase; D008156:Luciferases / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D012643:Selenium / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D016566:Organoselenium Compounds; C008493:methylselenic acid; D008156:Luciferases; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D012643:Selenium