Inhibition of NF-κB nuclear translocation via HO-1 activation underlies α-tocopheryl succinate toxicity
Inhibition of NF-κB nuclear translocation via HO-1 activation underlies α-tocopheryl succinate toxicity
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DOI：
10.1016/j.jnutbio.2011.10.012
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发表时间：
2012-12-01
影响因子：
5.6
通讯作者：
Minelli, Alba
中科院分区：
文献类型：
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作者：
Bellezza, Ilaria;Tucci, Arianna;Minelli, Alba
α -生育酚琥珀酸酯（α - tos）在线粒体复合体I和II水平上抑制氧化磷酸化，从而通过线粒体活性氧（ROS）的产生促进癌细胞死亡。氧化还原失衡激活NF-E2 p45相关因子2 (Nrf2)，这是一种参与细胞保护和解毒反应的转录因子。在这里，我们研究了血红素加氧酶-1 （HO-1）通过短时间暴露于α - tos在前列腺癌细胞中参与核因子κ B （nf - κ B）信号传导的调节。短期（4小时）暴露于α - tos会导致细胞活力显著降低（76%+/- 9%），ROS生成适度增加（113%+/- 8%）。α - tos通过诱导双相效应改变谷胱甘肽（GSH）稳态，即细胞内GSH含量在早期（1 h）下降（56%+/- 20%），随后在4 h时上升3倍。α - tos增加核易位和Nrf2亲电响应/抗氧化响应元件结合活性，导致下游基因胱氨酸-谷氨酸交换转运体和HO-1的上调，同时减少NF-kappa B核易位。这种作用被HO-1的药理学抑制所抑制，并被HO活性的最终产物，即胆红素和一氧化碳所模拟。结果表明，α - tos诱导的nf - κ B核易位抑制机制是由HO-1上调引起的。(C) 2012爱思唯尔公司版权所有。
alpha-Tocopheryl succinate (alpha-TOS) inhibits oxidative phosphorylation at the level of mitochondrial complex I and II, thus promoting cancer cell death through mitochondrial reactive oxygen species (ROS) generation. Redox imbalance activates NF-E2 p45-related factor 2 (Nrf2), a transcription factor involved in cell protection and detoxification responses. Here we examined the involvement of heme oxygenase-1 (HO-1) in the regulation of nuclear factor kappa B (NF-kappa B) signaling by short exposure to alpha-TOS in prostate cancer cells. A short-term (4 h) exposure to alpha-TOS causes a significant reduction in cell viability (76%+/- 9%) and a moderate rise in ROS production (113%+/- 8%). alpha-TOS alters glutathione (GSH) homeostasis by inducing a biphasic effect, i.e., an early (1 h) decrease in intracellular GSH content (56%+/- 20%) followed by a threefold rise at 4 h. alpha-TOS increases nuclear translocation and electrophileresponsive/antioxidant-responsive elements binding activity of Nrf2, resulting in up-regulation of downstream genes cystine-glutamic acid exchange transporter and HO-1, while decreasing NF-kappa B nuclear translocation. This effect is suppressed by the pharmacological inhibition of HO-1 and mimicked by the end-products of HO activity, i.e., bilirubin and carbon monoxide. Results suggest a little understood mechanism for alpha-TOS-induced inhibition of NF-kappa B nuclear translocation due to HO-1 up-regulation. (C) 2012 Elsevier Inc. All rights reserved.