Integrin αVβ3 contains a receptor site for resveratrol

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. [C-14]-Resveratrol binds to commercially purified integrin alpha V beta 3 and to alpha V beta 3 prepared from MCF-7 cells; binding of [C-14]- 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.