Abstract
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. J. Cell. Biochem. 104: 2131–2142, 2008. © 2008 Wiley‐Liss, Inc.