Title

Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein

Authors

Authors

A. Kotha; M. Sekharam; L. Cilenti; K. Siddiquee; A. Khaled; A. S. Zervos; B. Carter; J. Turkson;R. Jove

Comments

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Abbreviated Journal Title

Mol. Cancer Ther.

Keywords

PROSTATE-CANCER CELLS; CHEMOPREVENTIVE AGENT RESVERATROL; BREAST-CARCINOMA CELLS; DNA-BINDING ACTIVITY; NF-KAPPA-B; CONSTITUTIVE; ACTIVATION; MOLECULAR TARGETS; LNCAP CELLS; ANTIESTROGENIC PROPERTIES; ENDOTHELIAL-CELLS; Oncology

Abstract

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 GO-G, 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.

Journal Title

Molecular Cancer Therapeutics

Volume

5

Issue/Number

3

Publication Date

1-1-2006

Document Type

Article

Language

English

First Page

621

Last Page

629

WOS Identifier

WOS:000236444500017

ISSN

1535-7163

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