Carcinogenesis Advance Access published online on November 4, 2007
Carcinogenesis, doi:10.1093/carcin/bgm239
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RESVERATROL IS PRO-APOPTOTIC AND THYROID HORMONE IS ANTI-APOPTOTIC IN GLIOMA CELLS: BOTH ACTIONS ARE INTEGRIN- AND ERK-MEDIATED
1 Ordway Research Institute, Albany, NY
2 Research Service, Stratton Veterans Affairs Medical Center, Albany, NY
3 Department of Radiation Oncology, the Cleveland Clinic, Cleveland, OH
* To whom correspondence should be addressed at: The Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208, USA, Tel: 518-641-6428, E-mail: hlin{at}ordwayresearch.org
The stilbene resveratrol initiates p53-dependent apoptosis via plasma membrane integrin 
Vß3 in human cancer cells. A thyroid hormone (L-thyroxine, T4) membrane receptor also exists on Vß3. Stilbene and T4 signals are both transduced by extracellular-regulated kinases 1 and 2 (ERK1/2); however, T4 promotes cell proliferation in cancer cells, whereas resveratrol is pro-apoptotic. Thyroid hormone has been shown to interfere with resveratrol-induced apoptosis. However, the mechanisms involved are not fully understood. In this study, we examined the mechanism whereby T4 inhibits resveratrol-induced apoptosis in glioma cells. Resveratrol activated cPKC and ERK1/2 and caused nuclear localization of COX-2, consequent p53 phosphorylation and apoptosis. Resveratrol-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 resveratrol-treated cells. T4 inhibited resveratrol-induced nuclear COX-2 and cytosolic pro-apoptotic protein, BcL-x-s accumulation. Furthermore, T4 inhibited resveratrol-induced apoptosis by interfering with the interaction of nuclear COX-2 and ERK1/2. This effect of T4 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 T4, affect induction of apoptosis by resveratrol. Thus, the receptor sites on Vß3 for resveratrol and thyroid hormone are discrete and activate ERK1/2-dependent downstream effects on apoptosis that are distinctive.
Received July 16, 2007; revised October 3, 2007; accepted October 19, 2007.
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