Role of the Nrf2-heme oxygenase-1 pathway in silver nanoparticle-mediated cytotoxicity

Title
Role of the Nrf2-heme oxygenase-1 pathway in silver nanoparticle-mediated cytotoxicity
Author(s)
곽미경Su Jin Kang[Su Jin Kang]류인근Young Joon Lee[Young Joon Lee]
Keywords
FORKHEAD TRANSCRIPTION FACTOR; DNA-DAMAGE RESPONSE; HUMAN BREAST-CANCER; HEME OXYGENASE-1; OXIDATIVE STRESS; PROTEASOMAL DEGRADATION; SIGNALING PATHWAY; HEPATOMA-CELLS; GENE PROMOTER; BASAL LEVEL
Issue Date
201201
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Citation
TOXICOLOGY AND APPLIED PHARMACOLOGY, v.258, no.1, pp.89 - 98
Abstract
Silver nanoparticles (nano-Ag) have been widely used in various commercial products including textiles, electronic appliances and biomedical products. However, there remains insufficient information on the potential risk of nano-Ag to human health and environment. In the current study, we have investigated the role of NF-E2-related factor 2 (Nrf2) transcription factor in nano-Ag-induced cytotoxicity. When Nrf2 expression was blocked using interring RNA expression in ovarian carcinoma cell line, nano-Ag treatment showed a substantial decrease in cell viability with concomitant increases in apoptosis and DNA damage compared to the control cells. Target gene analysis revealed that the expression of heme oxygenase-1 (HO-1) was highly elevated by nano-Ag in nonspecific shRNA expressing cells, while Nrf2 knockdown cells (NRF2i) did not increase HO-1 expression. The role of HO-1 in cytoprotection against nano-Ag was reinforced by results using pharmacological inducer of HO-1: cobalt protoporphyrin-mediated HO-1 activation in the NRF2i cells prevented nano-Ag-mediated cell death. Similarly, pharmacological or genetic inhibition of HO-1 in nonspecific control cells exacerbated nano-Ag toxicity. As the upstream signaling mechanism, nano-Ag required the phosphoinositide 3-kinase (PI3K) and p38MAPK signaling cascades for HO-1 induction. The treatment with either PI3K inhibitor or p38MAPK inhibitor suppressed HO-1 induction and intensified nano-Ag-induced cell death. Taken together, these results suggest that Nrf2-dependent HO-1 up-regulation plays a protective role in nano-Ag-induced DNA damage and consequent cell death. In addition, nano-Ag-mediated HO-1 induction is associated with the PI3K and p38MAPK signaling pathways. (C) 2011 Elsevier Inc. All rights reserved.
URI
http://hdl.handle.net/YU.REPOSITORY/30096http://dx.doi.org/10.1016/j.taap.2011.10.011
ISSN
0041-008X
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