Role of p53 and NF-κB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells

被引:254
作者
Hastak, K
Gupta, S
Ahmad, N
Agarwal, MK
Agarwal, ML
Mukhtar, H [1 ]
机构
[1] Univ Wisconsin, Dept Dermatol, Madison, WI 53706 USA
[2] Case Western Reserve Univ, Dept Environm Hlth Sci, Cleveland, OH 44106 USA
[3] Cleveland Clin, Dept Mol Biol, Learner Res Inst, Cleveland, OH 44106 USA
[4] Case Western Reserve Univ, Jim & Eillen Dicke Res Lab, Cleveland, OH 44106 USA
[5] Univ Hosp Cleveland, Inst Res, Cleveland, OH 44106 USA
关键词
epigallocatechin-3-gallate; prostate cancer; p53; NF-kappa B; Bax; Bcl-2; caspases; apoptosis;
D O I
10.1038/sj.onc.1206708
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We have recently shown that oral consumption of green tea polyphenols inhibits prostate carcinogenesis in transgenic mouse model of prostate cancer and suggested that induction of apoptosis in prostate cancer cells is responsible for these effects. Much of the chemopreventive effects of green tea are attributed to its major polyphenolic constituent (-) epigallocatechin-3-gallate (EGCG). In the present study, we report that EGCG-induced apoptosis in human prostate carcinoma LNCaP cells is mediated via modulation of two related pathways: (a) stabilization of p53 by phosphorylation on critical serine residues and p14(ARF)-mediated downregulation of murine double minute 2(MDM2) protein, and (b) negative regulation of NF-kappaB activity, thereby decreasing the expression of the proapoptotic protein Bcl-2. EGCG-induced stabilization of p53 caused an upregulation in its transcriptional activity, thereby resulting in activation of its downstream targets p21/WAF1 and Bax. Thus, EGCG had a concurrent effect on two important transcription factors p53 and NF-kappaB, causing a change in the ratio of Bax/Bcl-2 in a manner that favors apoptosis. This altered expression of Bcl-2 family members triggered the activation of initiator capsases 9 and 8 followed by activation of effector caspase 3. Activation of the caspases was followed by poly (ADP-ribose) polymerase cleavage and induction of apoptosis. Taken together, the data indicate that EGCG induces apoptosis in human prostate carcinoma cells by shifting the balance between pro- and antiapoptotic proteins in favor of apoptosis.
引用
收藏
页码:4851 / 4859
页数:9
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