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Research Articles: Therapeutics

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

¹ Research Service, Stratton Veterans Affairs Medical Center; ² Ordway Research Institute; ³ Wadsworth Center, New York State Department of Health, Albany, New York; and ⁴ National Laboratory Animal Center, National Applied Research Laboratory, Nakang, Taipei, Taiwan

Requests for reprints: Hung-Yun Lin, Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208. Phone: 518-641-6428; Fax: 518-641-6304. E-mail: hlin{at}ordwayresearch.org

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 Ser¹⁵-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 Ser¹⁵-phosphorylated p53 and p300, which facilitates apoptosis in resveratrol-treated breast cancer cells. [Mol Cancer Ther 2006;5(8):2034–42]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁵ H. J. Cao et al., submitted for publication.

⁶ Unpublished observations.

Received 4/19/06; revised 6/11/06; accepted 6/22/06.

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