title: Integrin alphaVbeta3 contains a receptor site for resveratrol.
abstract: 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 alphaVbeta3 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 alphaVbeta3, but not to alphaVbeta5, inhibits activation by resveratrol of ERK1/2 and p53 and consequent apoptosis in estrogen receptor-alpha (ERalpha) positive MCF-7, and ERalpha-negative MDA-MB231 cells. Resveratrol is displaced from the purified integrin by an RGD, but not RGE, peptide, and by alphaVbeta3 integrin-specific Ab. Resveratrol action is blocked by siRNAbeta3, but not by siRNAalphaV. [14C]-Resveratrol binds to commercially purified integrin alphaVbeta3 and to alphaVbeta3 prepared from MCF-7 cells; binding of [14C]-resveratrol to the beta3, but not to the alphaV monomer, is displaced by unlabeled resveratrol. In conclusion, binding of resveratrol to integrin alphaVbeta3, principally to the beta3 monomer, is essential for transduction of the stilbene signal into p53-dependent apoptosis of breast cancer cells.
authors.affiliation: Stratton Veterans Affairs Medical Center, Albany, New York, USA.
authors.forename: Hung-Yun
authors.initials: HY
authors.lastname: Lin
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lansing
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Merillon
authors.forename: Faith B
authors.initials: FB
authors.lastname: Davis
authors.forename: Heng-Yuan
authors.initials: HY
authors.lastname: Tang
authors.forename: Ai
authors.initials: A
authors.lastname: Shih
authors.forename: Xavier
authors.initials: X
authors.lastname: Vitrac
authors.forename: Stephanie
authors.initials: S
authors.lastname: Krisa
authors.forename: Travis
authors.initials: T
authors.lastname: Keating
authors.forename: H James
authors.initials: HJ
authors.lastname: Cao
authors.forename: Joel
authors.initials: J
authors.lastname: Bergh
authors.forename: Steven
authors.initials: S
authors.lastname: Quackenbush
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Davis
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000493:pharmacokinetics* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53
chemical_list: D039302:Integrin alphaVbeta3; D039661:Integrin beta3; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D000077185:Resveratrol