title: AICAR induces Nrf2 activation by an AMPK-independent mechanism in hepatocarcinoma cells.
abstract: Hepatocellular carcinoma is one of the most frequent tumor types worldwide and oxidative stress represents a major risk factor in pathogenesis of liver diseases leading to HCC. Nuclear factor erythroid 2-related factor (Nrf2) is a transcription factor activated by oxidative stress that governs the expression of many genes which constitute the antioxidant defenses of the cell. In addition, oxidative stress activates AMP-activated protein kinase (AMPK), which has emerged in recent years as a kinase that controls the redox-state of the cell. Since both AMPK and Nrf2 are involved in redox homeostasis, we investigated whether there was a crosstalk between the both signaling systems in hepatocarcinoma cells. Here, we demonstrated that AMPK activator AICAR, in contrary to the A769662 allosteric activator, induces Nrf2 activation and concomitantly modulates the basal redox state of the hepatocarcinoma cells. When the expression of Nrf2 is knocked down, AICAR failed to induce its effect on redox state. These data highlight a major role of Nrf2 signaling pathway in mediating the AICAR effect on basal oxidative state. Furthermore, we demonstrated that AICAR metabolization by the cell is required to induce Nrf2 activation while, the silencing of AMPK does not have any effect on Nrf2 activation. This suggests that AICAR-induced Nrf2 activation is independent of AMPK activity. In conclusion, we identified AICAR as a potent modulator of the redox state of human hepatocarcinoma cells, via the Nrf2 signaling pathway and in an AMPK-independent mechanism.
authors: Toxicology and Cancer Biology Research Group GTOX, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
authors: Brice
authors: B
authors: Sid
authors: Toxicology and Cancer Biology Research Group GTOX, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
authors: Christophe
authors: C
authors: Glorieux
authors: Toxicology and Cancer Biology Research Group GTOX, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
authors: Manuel
authors: M
authors: Valenzuela
authors: Laboratory of Biochemistry and Cell Biology (URBC), NARILIS (NAmur Research Institute for Life Sciences), University of Namur (UNamur), Namur, Belgium.
authors: Guillaume
authors: G
authors: Rommelaere
authors: Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium.
authors: Mustapha
authors: M
authors: Najimi
authors: Toxicology and Cancer Biology Research Group GTOX, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
authors: Nicolas
authors: N
authors: Dejeans
authors: Laboratory of Biochemistry and Cell Biology (URBC), NARILIS (NAmur Research Institute for Life Sciences), University of Namur (UNamur), Namur, Belgium.
authors: Patricia
authors: P
authors: Renard
authors: Toxicology and Cancer Biology Research Group GTOX, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
authors: Julien
authors: J
authors: Verrax
authors: Toxicology and Cancer Biology Research Group GTOX, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium; Facultad de Ciencias de la Salud, Universidad Arturo Prat, Iquique, Chile. Electronic address: pedro.buccalderon@uclouvain.be.
authors: Pedro Buc
authors: PB
authors: Calderon
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D001713:Biphenyl Compounds; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000378:metabolism*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D020868:Gene Silencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011753:Pyrones / Q000494:pharmacology; D012263:Ribonucleosides / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D001713:Biphenyl Compounds; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011753:Pyrones; D012263:Ribonucleosides; D013876:Thiophenes; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D055372:AMP-Activated Protein Kinases; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile
keywords: AICAR; AMPK; Hepatocarcinoma cells; Nrf2; Redox homeostasis