Resveratrol causes COX-2- and p53-dependent apoptosis in head and neck squamous cell cancer cells.
Cyclooxygenase-2 (COX-2) content is increased in many types of tumor cells. We have investigated the mechanism by which resveratrol, a stilbene that is pro-apoptotic in many tumor cell lines, causes apoptosis in human head and neck squamous cell carcinoma UMSCC-22B cells by a mechanism involving cellular COX-2. UMSCC-22B cells treated with resveratrol for 24 h, with or without selected inhibitors, were examined: (1) for the presence of nuclear activated ERK1/2, p53 and COX-2, (2) for evidence of apoptosis, and (3) by chromatin immunoprecipitation to demonstrate p53 binding to the p21 promoter. Stilbene-induced apoptosis was concentration-dependent, and associated with ERK1/2 activation, serine-15 p53 phosphorylation and nuclear accumulation of these proteins. These effects were blocked by inhibition of either ERK1/2 or p53 activation. Resveratrol also caused p53 binding to the p21 promoter and increased abundance of COX-2 protein in UMSCC-22B cell nuclei. Resveratrol-induced nuclear COX-2 accumulation was dependent upon ERK1/2 activation, but not p53 activation. Activation of p53 and p53-dependent apoptosis were blocked by the COX-2 inhibitor, NS398, and by transfection of cells with COX-2-siRNA. In UMSCC-22B cells, resveratrol-induced apoptosis and induction of nuclear COX-2 accumulation share dependence on the ERK1/2 signal transduction pathway. Resveratrol-inducible nuclear accumulation of COX-2 is essential for p53 activation and p53-dependent apoptosis in these cancer cells.
Lin
Hung-Yun
HY
Signal Transduction Laboratory, Ordway Research Institute, 150 New Scotland Avenue, Albany, New York 12208, USA. hlin@ordwayresearch.org
Sun
Mingzeng
M
Tang
Heng-Yuan
HY
Simone
Tessa M
TM
Wu
Yun-Hsuan
YH
Grandis
Jennifer R
JR
Cao
H James
HJ
Davis
Paul J
PJ
Davis
Faith B
FB
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008954:Models, Biological; D018307:Neoplasms, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D009578:Nitrobenzenes / Q000494:pharmacology; D010768:Phosphoserine / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology; D013449:Sulfonamides / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D009578:Nitrobenzenes; D047428:Protein Kinase Inhibitors; D013267:Stilbenes; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D010768:Phosphoserine; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077185:Resveratrol