Journal article
Antioncogenic and Oncogenic Properties of Nrf2 in Arsenic-induced Carcinogenesis
The Journal of biological chemistry, Vol.290(45), pp.27090-27100
11/06/2015
DOI: 10.1074/jbc.M115.675371
PMCID: PMC4646382
PMID: 26385919
Abstract
Arsenic (As3+) is a carcinogen with considerable environmental and occupational relevancy. The present study shows that As3+-transformed human lung bronchial epithelial BEAS-2B cells (AsT cells) exhibit the property of apoptosis resistance. The level of basal reactive oxygen species (ROS) is very low in AsT cells in correlation with elevated expressions of both antioxidant enzymes and antiapoptotic proteins. Nuclear factor erythroid 2-related factor (Nrf2) and p62 are constitutively expressed. These two proteins up-regulate antioxidant enzymes and antiapoptotic proteins. The knockdown of Nrf2 or p62 by small interfering RNA (siRNA) enhanced both ROS levels and As3+-induced apoptosis in transformed cells. AsT cells have autophagy deficiency as evidenced by reduced formation of microtubule-associated protein 1 light chain 3 (LC3)-II, GFP-LC3 puncta, and autophagy flux. Results obtained using a soft agar assay and shRNA Nrf2-transfected cells show that Nrf2 plays an antioncogenic role before transformation, whereas this transcription factor plays an oncogenic role after transformation. In addition, depletion of Nrf2 by shRNA dramatically inhibited growth and proliferation of transformed cells. Furthermore, the Nrf2 protein levels and antiapoptotic and antioxidant enzyme levels are higher in lung adenocarcinoma than in normal tissues. Collectively, this study demonstrates that a constitutively high level of Nrf2 in AsT cells up-regulates the antioxidant proteins catalase and superoxide dismutase as well as the antiapoptotic proteins Bcl-2 and Bcl-xL. The final consequences are decreased ROS generation and increased apoptotic resistance, cell survival and proliferation, and tumorigenesis.
Background: Arsenic induced cell transformation and carcinogenesis.
Results: Arsenic-transformed cells have the property of apoptosis/autophagy resistance.
Conclusion: The constitutive activation of Nrf2 in arsenic-transformed cells up-regulates antioxidants, decreases ROS generation, and causes apoptosis resistance and tumorigenesis.
Significance: Antioncogenic role of inducible Nrf2 in normal cells and oncogenic role of constitutive activation of Nfr2 in cancer cells may increase our understanding of the mechanism of arsenic carcinogenesis and its prevention.
Details
- Title: Subtitle
- Antioncogenic and Oncogenic Properties of Nrf2 in Arsenic-induced Carcinogenesis
- Creators
- Young-Ok Son - University of KentuckyPoyil Pratheeshkumar - University of KentuckyRam Vinod Roy - University of KentuckyJohn Andrew Hitron - University of KentuckyLei Wang - University of KentuckySasidharan Padmaja Divya - University of KentuckyMei Xu - University of KentuckyJia Luo - University of KentuckyGang Chen - University of KentuckyZhuo Zhang - University of KentuckyXianglin Shi - University of Kentucky
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.290(45), pp.27090-27100
- DOI
- 10.1074/jbc.M115.675371
- PMID
- 26385919
- PMCID
- PMC4646382
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Grant note
- R01 ES025515 / National Institutes of Health
- Language
- English
- Date published
- 11/06/2015
- Academic Unit
- Pathology
- Record Identifier
- 9984201246702771
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