Integrin alphaVbeta3 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 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.
Lin
Hung-Yun
HY
Stratton Veterans Affairs Medical Center, Albany, New York, USA.
Lansing
Lawrence
L
Merillon
Jean-Michel
JM
Davis
Faith B
FB
Tang
Heng-Yuan
HY
Shih
Ai
A
Vitrac
Xavier
X
Krisa
Stephanie
S
Keating
Travis
T
Cao
H James
HJ
Bergh
Joel
J
Quackenbush
Steven
S
Davis
Paul J
PJ
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
D039302:Integrin alphaVbeta3; D039661:Integrin beta3; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D000077185:Resveratrol