Lin Hung-Yun, Tang Heng-Yuan, Keating Travis, Wu Yun-Hsuan, Shih Ai, Hammond Douglas, Sun Mingzeng, Hercbergs Aleck, Davis Faith B, Davis Paul J
Signal Transduction Laboratory, Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208, USA.
Carcinogenesis. 2008 Jan;29(1):62-9. doi: 10.1093/carcin/bgm239. Epub 2007 Nov 4.
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.
芪类化合物白藜芦醇（RV）通过人癌细胞质膜整合素αVβ3启动p53依赖性凋亡。甲状腺激素（L-甲状腺素，T4）膜受体也存在于αVβ3上。芪类化合物和T4信号均由细胞外调节激酶1和2（ERK1/2）转导；然而，T4促进癌细胞增殖，而RV具有促凋亡作用。甲状腺激素已被证明会干扰RV诱导的凋亡。然而，其中涉及的机制尚未完全了解。在本研究中，我们研究了T4抑制胶质瘤细胞中RV诱导凋亡的机制。RV激活传统蛋白激酶C和ERK1/2，并导致环氧合酶-2（COX-2）的核定位、随后的p53磷酸化和凋亡。RV诱导的ERK1/2激活不仅参与COX-2表达，还参与核COX-2积累。COX-2抑制剂NS-398不影响ERK1/2激活，但降低了COX-2蛋白的核丰度以及核COX-2与活化的ERK1/2复合物的形成，而这些复合物是RV处理细胞中p53依赖性凋亡所必需的。T4抑制RV诱导的核COX-2和细胞质促凋亡蛋白BcLx-s的积累。此外，T4通过干扰核COX-2与ERK1/2的相互作用来抑制RV诱导的凋亡。甲状腺激素与整合素受体结合的抑制剂四碘甲状腺乙酸（tetrac）可阻止T4的这种作用。在没有T4的情况下，tetrac不影响RV诱导的凋亡。因此，αVβ3上RV和甲状腺激素的受体位点是离散的，并激活对凋亡具有独特性的ERK1/2依赖性下游效应。
