Nicotine modulates the effects of retinoids on growth inhibition and RARβ expression in lung cancer cells
Nicotine modulates the effects of retinoids on growth inhibition and RARβ expression in lung cancer cells
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DOI：
10.1002/ijc.10304
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发表时间：
2002-05-10
影响因子：
6.4
通讯作者：
Zhang, XK
中科院分区：
文献类型：
--
作者：
Chen, GQ;Lin, BZ;Zhang, XK
流行病学和动物研究表明，维生素A及其天然和合成衍生物类维生素A是预防烟草相关癌症发展的有效药物。不幸的是，类维生素A对吸烟者的临床试验显示缺乏预防肺癌的功效。在我们的研究中，我们研究了尼古丁对全反式维甲酸（trans-RA）在人肺癌细胞中的抗癌活性的影响。我们的研究结果表明，尼古丁可以消除反式RA的生长抑制作用，通过抑制其诱导RA受体β（RAR β），肿瘤抑制因子的表达的能力。尼古丁的抑制作用伴随着孤儿受体TR 3的诱导。在H460肺癌细胞中通过过表达TR 3反义RNA来抑制TR 3表达，强烈地阻止了尼古丁对trans-RA活性的抑制作用。在瞬时转染试验中，尼古丁处理或TR 3表达载体的共转染抑制了trans-RA对RAR β启动子活性的诱导。RAR β启动子活性的抑制是由于TR 3与孤儿受体COUP-TF的相互作用，导致COUP-TF DNA结合的抑制和RAR β启动子的反式激活。此外，我们发现尼古丁未能抑制类维生素A X受体（RXR）选择性类维生素A SRI 1237对诱导生长抑制和RARP启动子活性的作用，这是由于SRI 1237能够通过RXR/TR 3异二聚体激活RARP β启动子。总之，我们的结果表明，尼古丁通过诱导TR 3表达来抑制RAR β表达，从而抑制反式RA的生长抑制作用，并表明RXR选择性类维生素A可能比经典类维生素A更有效地预防和治疗烟草相关癌症。(C)2002 Wiley-Liss，Inc.
Epidemiological and animal studies have demonstrated that vitamin A and its natural and synthetic derivatives, retinoids, are effective agents in preventing the development of tobacco-associated cancers. Unfortunately, clinical trials of retinoids on cigarette smokers have shown lack of efficacy in preventing lung cancer. In our study, we investigated the effect of nicotine on the anti-cancer activity of all trans-retinoic acid (trans-RA) in human lung cancer cells. Our results demonstrated that nicotine could abrogate the growth inhibitory effect of trans-RA by suppressing its ability to induce the expression of RA receptor beta (RARbeta), a tumor suppressor. The inhibitory effect of nicotine was accompanied with induction of orphan receptor TR3. Inhibition of TR3 expression by overexpression of TR3 anti-sense RNA in H460 lung cancer cells strongly prevented the suppressive effect of nicotine on trans-RA activity. Treatment with nicotine or the cotransfection of TR3 expression vector inhibited the induction of RARbeta promoter activity by trans-RA in transient transfection assays. The inhibition of RARbeta promoter activity was due to the interaction of TR3 with orphan receptor COUP-TF, resulting in inhibition of COUP-TF DNA binding and transactivation on the RARbeta promoter. Furthermore, we found that nicotine failed to suppress the effect of a retinoid X receptor (RXR)-selective retinoid SRI1237 on inducing both growth inhibition and RARP promoter activity, due to the ability of SRI 1237 to activate the RARbeta promoter through the RXR/TR3 heterodimer. Together, our results demonstrate that nicotine suppresses the growth inhibitory effects of trans-RA by inhibiting RARbeta expression through its induction of TR3 expression and suggest that RXR-selective retinoids may be more effective than classical retinoids for preventing and treating tobacco-associated cancers. (C) 2002 Wiley-Liss, Inc.