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¹ Molecular Oncology and ² Breast Cancer Programs, H. Lee Moffitt Cancer Center and Research Institute; ³ Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa; ⁴ BioMolecular Science Center, and ⁵ Department of Molecular Biology and Microbiology, University of Central Florida, Orlando, Florida; ⁶ Experimental Therapeutics Program, City of Hope Comprehensive Cancer Center, and ⁷ Division of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, California

Requests for reprints: James Turkson, BioMolecular Science Center, University of Central Florida, 12722 Research Parkway, Orlando, FL 32826. Phone: 407-882-2441; Fax: 407-384-2062. E-mail: jturkson{at}mail.ucf.edu

Resveratrol is a naturally occurring phytoalexin with antioxidant and antiinflammatory properties. Recent studies suggest that resveratrol possesses anticancer effects, although its mechanism of action is not well understood. We now show that resveratrol inhibits Src tyrosine kinase activity and thereby blocks constitutive signal transducer and activator of transcription 3 (Stat3) protein activation in malignant cells. Analyses of resveratrol-treated malignant cells harboring constitutively-active Stat3 reveal irreversible cell cycle arrest of v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), human breast (MDA-MB-231), pancreatic (Panc-1), and prostate carcinoma (DU145) cell lines at the G₀-G₁ phase or at the S phase of human breast cancer (MDA-MB-468) and pancreatic cancer (Colo-357) cells, and loss of viability due to apoptosis. By contrast, cells treated with resveratrol, but lacking aberrant Stat3 activity, show reversible growth arrest and minimal loss of viability. Moreover, in malignant cells harboring constitutively-active Stat3, including human prostate cancer DU145 cells and v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), resveratrol treatment represses Stat3-regulated cyclin D1 as well as Bcl-x_L and Mcl-1 genes, suggesting that the antitumor cell activity of resveratrol is in part due to the blockade of Stat3-mediated dysregulation of growth and survival pathways. Our study is among the first to identify Src-Stat3 signaling as a target of resveratrol, further defining the mechanism of antitumor cell activity of resveratrol and raising its potential application in tumors with an activated Stat3 profile. [Mol Cancer Ther 2006;5(3):621–9]

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Received 7/21/05; revised 12/12/05; accepted 1/11/06.