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.
Tang
Heng-Yuan
HY
Research Service, Stratton Veterns Affairs Medical Center, New York State Department of Health, Albany, New York, USA.
Shih
Ai
A
Cao
H James
HJ
Davis
Faith B
FB
Davis
Paul J
PJ
Lin
Hung-Yun
HY
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects* / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D000077185:Resveratrol; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D012694:Serine; D051546:Cyclooxygenase 2; D050881:E1A-Associated p300 Protein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077185:Resveratrol