Resveratrol and apoptosis.
Resveratrol is a naturally occurring stilbene with desirable cardioprotective and anti-cancer properties. We have demonstrated the existence of a plasma membrane receptor for resveratrol near the arginine-glycine-aspartate (RGD) recognition site on integrin α(v)β₃ that is involved in stilbene-induced apoptosis of cancer cells. Resveratrol treatment in vitro causes activation and nuclear translocation of mitogen-activated protein kinase (ERK1/2), consequent phosphorylation of Ser-15 of p53, and apoptosis. An RGD peptide blocks these actions of resveratrol. By a PD98059-inhibitable process, resveratrol causes inducible COX-2 to accumulate in the nucleus where it complexes with pERK1/2 and p53. Chromatin immunoprecipitation reveals binding of nuclear COX-2 to promoters of certain p53-responsive genes, including PIG3 and Bax. NS-398, a specific pharmacologic inhibitor of COX-2, prevents resveratrol-induced complexing of nuclear ERK1/2 with COX-2 and with pSer-15-p53 and subsequent apoptosis; cyclooxygenase enzyme activity is not involved. Molecular steps in the pro-apoptotic action of resveratrol in cancer cells include induction of intranuclear COX-2 accumulation relevant to activation of p53. Epidermal growth factor, estrogen, and thyroid hormone act downstream of ERK1/2 to prevent resveratrol-induced apoptosis.
Ordway Research Institute, Albany, New York 12208, USA. hlin@ordwayresearch.org
Hung-Yun
HY
Lin
Heng-Yuan
HY
Tang
Faith B
FB
Davis
Paul J
PJ
Davis
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013267:Stilbenes / Q000378:metabolism* / Q000494:pharmacology*
D039302:Integrin alphaVbeta3; D013267:Stilbenes; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases; D000077185:Resveratrol