title: Activation of transcription factor Nrf2 signalling by the sphingosine kinase inhibitor SKI-II is mediated by the formation of Keap1 dimers.
abstract: BACKGROUND
  Anti-oxidant capacity is crucial defence against environmental or endogenous oxidative stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that plays a key defensive role against oxidative and cytotoxic stress and cellular senescence. However, Nrf2 signalling is impaired in several aging-related diseases, such as chronic pulmonary obstructive disease (COPD), cancer, and neurodegenerative diseases. Thus, novel therapeutics that enhance Nrf2 signalling are an attractive approach to treat these diseases.
  
  
  RESULTS
  Nrf2 was stabilized by SKI-II (2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole), which is a known sphingosine kinase inhibitor, in human bronchial epithelial cell line, BEAS2B, and in primary human bronchial epithelial cells, leading to enhancement of anti-oxidant proteins, such as HO-1, NQO1 and GCLM. The activation of Nrf2 was achieved by the generation of inactive dimerized form of Keap1, a negative regulator of Nrf2 expression, which was independent of sphingosine kinase inhibition. Using mice that were exposed to cigarette smoke, SKI-II induced Nrf2 expression together with HO-1 in their lungs. In addition, SKI-II reduced cigarette smoke mediated oxidative stress, macrophages and neutrophil infiltration and markers of inflammation in mice.
  
  
  CONCLUSIONS
  SKI-II appears to be a novel activator of Nrf2 signalling via the inactivation of Keap1.
authors: Airway Disease Section, National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors: Nicolas
authors: N
authors: Mercado
authors: Department of Physiology and Anatomy, Nihon University School of Pharmacy, Funabashi, Chiba, Japan.
authors: Yasuo
authors: Y
authors: Kizawa
authors: Department of Physiology and Anatomy, Nihon University School of Pharmacy, Funabashi, Chiba, Japan.
authors: Keitaro
authors: K
authors: Ueda
authors: Department of Agricultural, Food and Nutritional Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors: Yeping
authors: Y
authors: Xiong
authors: Department of Physiology and Anatomy, Nihon University School of Pharmacy, Funabashi, Chiba, Japan.
authors: Genki
authors: G
authors: Kimura
authors: Department of Agricultural, Food and Nutritional Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors: Audric
authors: A
authors: Moses
authors: Department of Agricultural, Food and Nutritional Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors: Jonathan M
authors: JM
authors: Curtis
authors: Airway Disease Section, National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors: Kazuhiro
authors: K
authors: Ito
authors: Airway Disease Section, National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors: Peter J
authors: PJ
authors: Barnes
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D055503:Protein Multimerization; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012907:Smoking / Q000188:drug therapy / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D000099157:Sphingosine Kinase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D000099157:Sphingosine Kinase; C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol; C431364:KEAP1 protein, human; C495635:NFE2L2 protein, human