Genistein inhibits NF-kappa B activation in prostate cancer cells.
Prostate cancer is the second leading cause of cancer-related deaths in men in the United States. Epidemiological studies indicate that susceptibility to prostate cancer may be partly due to environmental influences, especially diet. An association has been shown between decreased prostate cancer risk and mortality with increased consumption of soy products, resulting in increased levels of isoflavones. We previously demonstrated that the soy isoflavone genistein inhibits cell growth and induces apoptosis in prostate cancer cells. To further elucidate the molecular mechanism by which genistein elicits its apoptotic effect, we investigated the role of a transcription factor, nuclear factor-kappa B (NF-kappa B), in the androgen-sensitive cell line LNCaP and the androgen-insensitive cell line PC3. Here we show that genistein decreases NF-kappa B DNA binding and abrogates NF-kappa B activation by DNA-damaging agents, H2O2 and tumor necrosis factor-alpha, in prostate cancer cells regardless of androgen sensitivity. Additionally, we have demonstrated that genistein reduces phosphorylation of the inhibitory protein I kappa B alpha and blocks the nuclear translocation of NF-kappa B, prohibiting DNA binding and preventing NF-kappa B activation. These results provide a mechanism by which genistein induces apoptosis in prostate cancer cells: the inactivation of NF-kappa B. Furthermore, genistein's ability to abrogate NF-kappa B activation by DNA-damaging agents strongly supports genistein's role as a chemopreventive agent.
Davis
J N
JN
Department of Cancer Biology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA.
Kucuk
O
O
Sarkar
F H
FH
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020672:I-kappa B Proteins; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D006861:Hydrogen Peroxide; D019833:Genistein