Genistein Inhibits NF-kappaB Activation in Prostate Cancer Cells

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TRANSCRIPTION factors
PROSTATE -- Cancer
SOY proteins -- Therapeutic use
APOPTOSIS -- Prevention
PHOSPHORYLATION
CHEMICAL inhibitors

Abstract:Abstract: 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-kappaB (NF-kappaB), in the androgen-sensitive cell line LNCaP and the androgen-insensitive cell line PC3. Here we show that genistein decreases NF-kappaB DNA binding and abrogates NF-kappaB activation by DNA-damaging agents, H[sub 2]O[sub 2] 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 IkappaBalpha and blocks the nuclear translocation of NF-kappaB, prohibiting DNA binding and preventing NF-kappaB activation. These results provide a mechanism by which genistein induces apoptosis in prostate cancer cells: the inactivation of NF-kappaB. Furthermore, genistein's ability to abrogate NF-kappaB activation by DNA-damaging agents strongly supports genistein's role as a chemopreventive agent.

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