Differential transcriptional regulation of hypoxia-inducible factor-1α by arsenite under normoxia and hypoxia: involvement of Nrf2.
Arsenite (As(III)) is widely distributed in nature and can be found in water, food, and air. There is significant evidence that exposure to As(III) is associated with human cancers originated from liver, lung, skin, bladder, kidney, and prostate. Hypoxia plays a role in tumor growth and aggressiveness; adaptation to it is, at least to a large extent, mediated by hypoxia-inducible factor-1α (HIF-1α). In the current study, we investigated As(III) effects on HIF-1α under normoxia and hypoxia in the hepatoma cell line HepG2. We found that As(III) increased HIF-1α protein levels under normoxia while the hypoxia-mediated induction of HIF1α was reduced. Thereby, the As(III) effects on HIF-1α were dependent on both, transcriptional regulation via the transcription factor Nrf2 mediated by NOX4, PI3K/Akt, and ERK1/2 as well as by modulation of HIF-1α protein stability. In line, the different effects of As(III) via participation of HIF-1α and Nrf2 were also seen in tube formation assays with endothelial cells where knockdown of Nrf2 and HIF-1α abolished As(III) effects. Overall, the present study shows that As(III) is a potent inducer of HIF-1α under normoxia but not under hypoxia which may explain, in part, its carcinogenic as well as anti-carcinogenic actions.



As(III) increased HIF-1α under normoxia but reduced its hypoxia-dependent induction. The As(III) effects on HIF-1α were dependent on ROS, NOX4, PI3K/Akt, and ERK1/2. The As(III) effects under normoxia involved transcriptional regulation via Nrf2. Knockdown of Nrf2 and HIF-1α abolished As(III) effects in tube formation assays. The data may partially explain As(III)'s carcinogenic and anti-carcinogenic actions.
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Aapistie 7, FI-90220, Oulu, Finland.
Zukaa
Z
Al Taleb
Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, Technical University Munich, Munich, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
Andreas
A
Petry
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Aapistie 7, FI-90220, Oulu, Finland.
Tabughang Franklin
TF
Chi
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Aapistie 7, FI-90220, Oulu, Finland.
Daniela
D
Mennerich
Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, Technical University Munich, Munich, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
Agnes
A
Görlach
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Aapistie 7, FI-90220, Oulu, Finland.
Elitsa Y
EY
Dimova
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Aapistie 7, FI-90220, Oulu, Finland. tkietzm@gwdg.de.
Thomas
0000-0003-0242-8636
T
Kietzmann
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018053:Arsenites / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology; D015687:Cell Hypoxia / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; D051267:NF-E2-Related Factor 2; D019869:Phosphatidylinositol 3-Kinases; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D018053:Arsenites; D002273:Carcinogens; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017395:Plasminogen Activator Inhibitor 1; D017382:Reactive Oxygen Species; D051547:Heme Oxygenase-1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C015001:arsenite
Arsenite As(III); Hypoxia-inducible factor 1 (HIF-1α); Mitogen-activated protein kinase (MAPK); NADPH enzyme oxidase 4 (NOX4); Reactive oxygen species (ROS)