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

Cyclooxygenase-2 (COX-2) is antiapoptotic and is implicated in tumorigenesis. Recent reports, however, have also ascribed a proapoptotic action to inducible COX-2. We show here for the first time that a stilbene, resveratrol, induces nuclear accumulation of COX-2 protein in human breast cancer MCF-7 and MDA-MB-231 cell cultures. The induction of ...
COX-2 accumulation by resveratrol is mitogen-activated protein kinase (MAPK; extracellular signal-regulated kinase 1/2)- and activator protein 1- dependent. Nuclear COX-2 in resveratrol-treated cells colocalizes with Ser(15)-phosphorylated p53 and with p300, a coactivator for p53-dependent gene expression. The interaction of COX-2, p53, and p300, as well as resveratrol-induced apoptosis, was inhibited by a MAPK activation inhibitor, PD98059. A specific inhibitor of COX-2, NS398, and small interfering RNA knockdown of COX-2 were associated with reduced p53 phosphorylation and consequent decrease in p53-dependent apoptosis in resveratrol-treated cells. We conclude that nuclear accumulation of COX-2 can be induced by resveratrol and that the COX has a novel intranuclear colocalization with Ser(15)-phosphorylated p53 and p300, which facilitates apoptosis in resveratrol-treated breast cancer cells.
Mesh Terms:
Antineoplastic Agents, Phytogenic, Apoptosis, Breast Neoplasms, Cell Nucleus, Cyclooxygenase 2, E1A-Associated p300 Protein, Female, Humans, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Phosphorylation, Serine, Signal Transduction, Stilbenes, Transcription Factor AP-1, Tumor Cells, Cultured, Tumor Suppressor Protein p53
Mol. Cancer Ther.
Date: Aug. 01, 2006
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