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Molecular Mechanisms of Resveratrol Action in Lung Cancer Cells Using Dual Protein and Microarray Analyses

Carcinogenesis and Chemoprevention Division, IIT Research Institute, Chicago, Illinois

Requests for reprints: Rajendra G. Mehta, IIT Research Institute, 10 West 35th Street, Chicago, IL 60616. Phone: 312-567-4970; Fax: 312-567-4931; E-mail: RMehta{at}iitri.org.

Resveratrol, a natural phytoestrogen found in red wine and a variety of plants, is reported to have protective effects against lung cancer; however, there is little work directed toward the understanding of the mechanism of its action in this disease. In this study, we used a combination of experimental approaches to understand the biological activity and molecular mechanisms of resveratrol. Microarray gene expression profiling and high-throughput immunoblotting (PowerBlot) methodologies were employed to gain insights into the molecular mechanisms of resveratrol action in human lung cancer cells. In this report, we confirm the up-regulation of p53 and p21 and the induction of apoptosis by the activation of the caspases and the disruption of the mitochondrial membrane complex. We show the arrest of A549 cells in the G₁ phase of cell cycle in the presence of resveratrol and also report alterations in both gene and protein expressions of cyclin A, chk1, CDC27, and Eg5. Furthermore, the results indicated that resveratrol action is mediated via the transforming growth factor-β pathway, particularly through the Smad proteins. Results showed the down-regulation of the Smad activators 2 and 4 and the up-regulation of the repressor Smad 7 as a result of resveratrol treatment. Resveratrol is a potent inhibitor of A549 lung cancer cell growth, and our results suggest that resveratrol may be a promising chemopreventive or chemotherapeutic agent for lung cancer. [Cancer Res 2007;67(24):12007–17]