Oestrogen inhibits resveratrol-induced post-translational modification of p53 and apoptosis in breast cancer cells

Abstract

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 17β-oestradiol (E2) further enhanced MAPK activation, but E2 blocked resveratrol-induced apoptosis, as measured by nucleosome ELISA and DNA fragmentation assays. E2 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 E2 on resveratrol action were blocked by ICI 182,780 (ICI), an inhibitor of the nuclear oestrogen receptor-α (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 E2 inhibited resveratrol-induced, p53-directed transcriptional activity. These results suggest that E2 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 E2-depleted and -repleted environments.

Resveratrol-induced cyclooxygenase-2 facilitates p53-dependent apoptosis in human breast cancer cells

“…We have previously reported an essential role of mitogen-activated protein kinase (MAPK), specifically ERK1/2, in resveratrol-induced Ser 15 phosphorylation of p53 and resulting apoptosis in MCF-7 cells (8). In the studies illustrated in Fig.…”

“…Apoptosis of cancer cells induced by resveratrol requires posttranslational modification of p53, including phosphorylation and acetylation (8). Ser 15 phosphorylation of p53 is dependent on the activation of MAPKs (ERKs; refs.…”

“…The compound has anticancer properties and is capable of inducing apoptosis (2) and conferring cardiovascular protection (3) and neuroprotection (4). We have reported that resveratrol induces p53-dependent apoptosis in several different cancer cell lines, including cells derived from cancer of the prostate (5,6), thyroid (7), and breast (8). We have also described a cell surface receptor for resveratrol, which is linked to activation of p53 and apoptosis in MCF-7 human breast cancer cells (9).…”

Resveratrol as a Chemopreventive Agent: A Promising Molecule for Fighting Cancer

“…A direct effect on apoptosis by downregulating bcl-2 expression and upregulating bax expression with p53 can occur and activate caspases [188]. It appears that resveratrol can induce an increase in the tumor suppressor gene p53 in various cell types [189][190][191] and induce its phosphorylation [62,[74][75][76]192,193]. This activation of the transcription factor p53 by resveratrol could contribute to death and cell cycle arrest [53,73,74], but the polyphenol can also induce apoptosis in p53-deficient cells [194,195], indicating that p53 is not an absolute requirement for the cytotoxic effect of the molecule.…”

Chemically-Induced DNA Damage, Mutagenesis, and Cancer

“…Resveratrol activates ERK1/2 at low concentrations (1 pM-10 μM), but at higher concentrations (50-100 μM) can inhibit MAPK in human neuroblastoma SH-SY5Y cells [142]. In contrast, resveratrol activates ERK1/2 in prostate [143], breast [144,145], glial [146], head and neck [147], and ovarian cancer cells [148]. MAPKs in a constitutively active state are necessary to maintain the malignant state; however, short-term activation of MAPK may drive the cells to apoptosis [149].…”