Zinc inhibits nuclear factor-kappa B activation and sensitizes prostate cancer cells to cytotoxic agents.
Prostate carcinogenesis involves transformation of zinc-accumulating normal epithelial cells to malignant cells, which do not accumulate zinc. In this study, we demonstrate by immunoblotting and immunohistochemistry that physiological levels of zinc inhibit activation of nuclear factor (NF)-kappa B transcription factor in PC-3 and DU-145 human prostate cancer cells, reduce expression of NF-kappa B-controlled antiapoptotic protein c-IAP2, and activate c-Jun NH(2)-terminal kinases. Preincubation of PC-3 cells with physiological concentrations of zinc sensitized tumor cells to tumor necrosis factor (TNF)-alpha, and paclitaxel mediated cell death as defined by terminal deoxynucleotidyl transferase-mediated nick end labeling assay. These results suggest one possible mechanism for the inhibitory effect of zinc on the development and progression of prostate malignancy and might have important consequences for the prevention and treatment of prostate cancer.
Uzzo
Robert G
RG
Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Leavis
Paul
P
Hatch
William
W
Gabai
Vladimir L
VL
Dulin
Nickolai
N
Zvartau
Nadezhda
N
Kolenko
Vladimir M
VM
D021581:Active Transport, Cell Nucleus; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D017239:Paclitaxel / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011506:Proteins / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology*
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D015032:Zinc; D017239:Paclitaxel