Role of the Nrf2-heme oxygenase-1 pathway in silver nanoparticle-mediated cytotoxicity.
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.
Yeungnam University, College of Pharmacy, Gyeongsan-si, Gyeongsangbuk-do 712-749, Republic of Korea.
Su Jin
SJ
Kang
In-Geun
IG
Ryoo
Young Joon
YJ
Lee
Mi-Kyoung
MK
Kwak
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D051547:Heme Oxygenase-1 / Q000502:physiology*; D006801:Humans; D053768:Metal Nanoparticles / Q000633:toxicity*; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D012834:Silver / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012834:Silver; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases