The stilbene resveratrol (RV) initiates p53-dependent apoptosis via plasma membrane integrin alphaVbeta3 in human cancer cells. A thyroid hormone (L-thyroxine, T(4)) membrane receptor also exists on alphaVbeta3. Stilbene and T(4) signals are both transduced by extracellular-regulated kinases 1 and 2 (ERK1/2); however, T(4) promotes cell proliferation in cancer cells, whereas RV is pro-apoptotic. Thyroid hormone has been shown to interfere with RV-induced apoptosis. However, the mechanisms involved are not fully understood. In this study, we examined the mechanism whereby T(4) inhibits RV-induced apoptosis in glioma cells. RV activated conventional protein kinase C and ERK1/2 and caused nuclear localization of cyclooxygenase-2 (COX-2), consequent p53 phosphorylation and apoptosis. RV-induced ERK1/2 activation is involved in not only COX-2 expression but also nuclear COX-2 accumulation. NS-398, a COX-2 inhibitor, did not affect ERK1/2 activation, but reduced the nuclear abundance of COX-2 protein and the formation of complexes of nuclear COX-2 and activated ERK1/2 that are required for p53-dependent apoptosis in RV-treated cells. T(4) inhibited RV-induced nuclear COX-2 and cytosolic pro-apoptotic protein, BcLx-s, accumulation. Furthermore, T(4) inhibited RV-induced apoptosis by interfering with the interaction of nuclear COX-2 and ERK1/2. This effect of T(4) was prevented by tetraiodothyroacetic acid (tetrac), an inhibitor of the binding of thyroid hormone to its integrin receptor. Tetrac did not, in the absence of T(4), affect induction of apoptosis by RV. Thus, the receptor sites on alphaVbeta3 for RV and thyroid hormone are discrete and activate ERK1/2-dependent downstream effects on apoptosis that are distinctive.