Inhibition of NF-κB nuclear translocation via HO-1 activation underlies α-tocopheryl succinate toxicity

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.