Oestrogen inhibits resveratrol-induced post-translational modification of p53 and apoptosis in breast cancer cells.
Resveratrol, a naturally occurring stilbene, induced apoptosis in human breast cancer MCF-7 cells. The mechanism of this effect was dependent on mitogen-activated protein kinase (MAPK, ERK1/2) activation and was associated with serine phosphorylation and acetylation of p53. Treatment of MCF-7 cells with resveratrol in the presence of 17beta-oestradiol (E(2)) further enhanced MAPK activation, but E(2) blocked resveratrol-induced apoptosis, as measured by nucleosome ELISA and DNA fragmentation assays. E(2) inhibited resveratrol-stimulated phosphorylation of serines 15, 20 and 392 of p53 and acetylation of p53 in a concentration- and time-dependent manner. These effects of E(2) on resveratrol action were blocked by ICI 182,780 (ICI), an inhibitor of the nuclear oestrogen receptor-alpha (ER). ICI 182,780 did not block the actions of resveratrol, alone. Electrophoretic mobility studies of p53 binding to DNA and of p21 expression indicated that E(2) inhibited resveratrol-induced, p53-directed transcriptional activity. These results suggest that E(2) inhibits p53-dependent apoptosis in MCF-7 cells by interfering with post-translational modifications of p53 which are essential for p53-dependent DNA binding and consequent stimulation of apoptotic pathways. These studies provide insight into the complex pathways by which apoptosis is induced by resveratrol in E(2)-depleted and -repleted environments.
Zhang
S
S
The Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208, USA.
Cao
H J
HJ
Davis
F B
FB
Tang
H-Y
HY
Davis
P J
PJ
Lin
H-Y
HY
D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D000077185:Resveratrol; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D013267:Stilbenes / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; D012264:Ribonucleotide Reductases; D000077185:Resveratrol