Differential transcriptional regulation of hypoxia-inducible factor-1α by arsenite under normoxia and hypoxia : involvement of Nrf2
|Author:||al Taleb, Zukaa1; Petry, Andreas2,3; Franklin Chi, Tabughang1;|
1Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
2Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, Technical University Munich, Munich, Germany
3DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
|Online Access:||PDF Full Text (PDF, 2.2 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe201702271879
|Publish Date:|| 2017-02-27
AbstractArsenite (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.
Journal of Molecular Medicine
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
Work of the authors is supported by grants from the Biocenter Oulu, the Sigrid Juselius Foundation, Jane and Aatos Erkko Foundation, Academy of Finland, and by the European Cooperation in Science and Technology (COST Action BM1203/EU‐ROS).
© The Author(s) 2016
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.