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Published online before print June 21, 2006 as doi: 10.1096/fj.06-5743fje.

Integrin {alpha}V{beta}3 contains a receptor site for resveratrol

Hung-Yun Lin, Lawrence Lansing, Jean-Michel Merillon, Faith B. Davis, Heng-Yuan Tang, Ai Shih, Xavier Vitrac, Stephanie Krisa, Travis Keating, H. James Cao, Joel Bergh, Steven Quackenbush, and Paul J. Davis

E-mail contact: fdavis@ordwayresearch.org

Resveratrol is a naturally occurring polyphenol, which causes apoptosis in cultured cancer cells. We describe a cell surface resveratrol receptor on the extracellular domain of hetero-dimeric {alpha}V{beta}3 integrin in MCF-7 human breast cancer cells. This receptor is linked to induction by resveratrol of extracellular-regulated kinases 1 and 2 (ERK1/2)- and serine-15-p53-dependent phosphorylation leading to apoptosis. The integrin receptor is near the Arg-Gly-Asp (RGD) recognition site on the integrin; an integrin-binding RGD peptide inhibits induction by resveratrol of ERK1/2- and p53-dependent apoptosis. Antibody (Ab) to integrin {alpha}V{beta}3, but not to {alpha}V{beta}5, inhibits activation by resveratrol of ERK1/2 and p53 and consequent apoptosis in estrogen receptor-{alpha} (ER{alpha}) positive MCF-7, and ER{alpha}-negative MDA-MB231 cells. Resveratrol is displaced from the purified integrin by an RGD, but not RGE, peptide, and by {alpha}V{beta}3 integrin-specific Ab. Resveratrol action is blocked by siRNA{beta}3, but not by siRNA{alpha}V. [14C]-Resveratrol binds to commercially purified integrin {alpha}V{beta}3 and to {alpha}V{beta}3 prepared from MCF-7 cells; binding of [14C]-resveratrol to the {beta}3, but not to the {alpha}V monomer, is displaced by unlabeled resveratrol. In conclusion, binding of resveratrol to integrin {alpha}V{beta}3, principally to the {beta}3 monomer, is essential for transduction of the stilbene signal into p53-dependent apoptosis of breast cancer cells.--Lin, H.-Y., Lansing, L., Merillon, J.-M., Davis, F. B., Tang, H.-Y., Shih, A., Vitrac, X., Krisa, S., Keating, T., Cao, H. J., Bergh, J., Quackenbush, S., Davis, P. J. Integrin {alpha}V{beta}3 contains a receptor site for resveratrol.




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