Inhibition of NF-¦ÊB nuclear translocation via HO-1 activation underlies ¦Á-tocopheryl succinate toxicity

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• 作者：Ilaria Bellezza^a ; ^{ilaria.bellezza@unipg.it} ; Arianna Tucci^a ; Francesco Galli^b ; Silvia Grottelli^a ; Anna Lisa Mierla^a ; Francesca Pilolli^b ; Alba Minelli^a
• 关键词：¦Á-TOH ; ¦Á-tocopherol ; ¦Á-TOS ; ¦Á-tocopheryl succinate ; BSO ; l-buthionine-(S ; R)-sulfoximine ; CO ; carbon monoxide ; CORM-2 ; tricarbonyldichlororuthenium (II) dimer ; DCFH-DA ; 2&prime ; 7&prime ; -dichlorodihydrofluorescein diacetate ; EpRE/ARE ; electrophile-resp
• 刊名：Journal of Nutritional Biochemistry
• 出版年：2012
• 出版时间：December, 2012
• 年：2012
• 卷：23
• 期：12
• 页码：1583-1591
• 全文大小：904 K

文摘

¦Á-Tocopheryl succinate (¦Á-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 ¦ÊB (NF-¦ÊB) signaling by short exposure to ¦Á-TOS in prostate cancer cells. A short-term (4 h) exposure to ¦Á-TOS causes a significant reduction in cell viability (76 % ¡À9 % ) and a moderate rise in ROS production (113 % ¡À8 % ). ¦Á-TOS alters glutathione (GSH) homeostasis by inducing a biphasic effect, i.e., an early (1 h) decrease in intracellular GSH content (56 % ¡À20 % ) followed by a threefold rise at 4 h. ¦Á-TOS increases nuclear translocation and electrophile-responsive/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-¦ÊB 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 ¦Á-TOS-induced inhibition of NF-¦ÊB nuclear translocation due to HO-1 up-regulation.