Carcinogenesis Advance Access originally published online on November 4, 2007
Carcinogenesis 2008 29(1):62-69; 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 Signal Transduction Laboratory, Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208, USA
2 Research Service, Stratton Veterans Affairs Medical Center, Albany, NY, USA
3 Department of Radiation Oncology, The Cleveland Clinic, Cleveland, OH, USA
* To whom correspondence should be addressed. Tel: +1 518 641 6428; Email: hlin{at}ordwayresearch.org
The stilbene resveratrol (RV) initiates p53-dependent apoptosis via plasma membrane integrin 
Vβ3 in human cancer cells. A thyroid hormone (L-thyroxine, T4) membrane receptor also exists on Vβ3. 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 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 T4 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. T4 inhibited RV-induced nuclear COX-2 and cytosolic pro-apoptotic protein, BcLx-s, accumulation. Furthermore, T4 inhibited RV-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 RV. Thus, the receptor sites on Vβ3 for RV and thyroid hormone are discrete and activate ERK1/2-dependent downstream effects on apoptosis that are distinctive.
Abbreviations: COX-2, cyclooxygenase-2; cPKC, conventional protein kinase C; ELISA, enzyme-linked immunoadsorbent assay; ERK1/2, extracellular-regulated kinases 1 and 2; FBS, fetal bovine serum; pERK12, phospho-ERK1/2; PMA, phorbol 12-myristate 13-acetate; RGD, arginine–glycine–aspartate; RGE, arginine-glycine-glutamate; RV, resveratrol; TCA, trichloroacetic acid; tetrac, tetraiodothyroacetic acid; T4, L-thyroxine
Received July 16, 2007; revised October 3, 2007; accepted October 19, 2007.
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