Long-term exposures to low doses of silver nanoparticles enhanced in vitro malignant cell transformation in non-tumorigenic BEAS-2B cells.
To predict carcinogenic potential of AgNPs on the respiratory system, BEAS-2B cells (human bronchial epithelial cells) were chronically exposed to low- and non-cytotoxic dose (0.13 and 1.33μg/ml) of AgNPs for 4months (#40 passages). To assess malignant cell transformation of chronic exposure to AgNPs, several bioassays including anchorage independent agar colony formation, cell migration/invasion assay, and epithelial-mesenchymal transition (EMT) were performed in BEAS-2B cells. Chronic exposure to AgNPs showed a significant increase of anchorage independent agar colony formation and cell migration/invasion. EMT, which is the loss of epithelial markers (E-Cadherin and Keratin) and the gain of mesenchymal marker (N-cadherin and Vimentin), was induced by chronic exposure to AgNPs. These responses indicated that chronic exposure to AgNPs could acquire characteristics of tumorigenic cells from normal BEAS-2B cells. In addition, caspase-3, p-p53, p-p38, and p-JNK were significantly decreased, while p-ERK1/2 was significantly increased. MMP-9 related to cell migration/invasion was upregulated, while a MMP-9 inhibitor, TIMP-1 was down-regulated. These results indicated that BEAS-2B cells exposed to AgNPs could induce anti-apoptotic response/anoikis resistance, and cell migration/invasion by complex regulation of MAPK kinase (p38, JNK, and ERK) and p53 signaling pathways. Therefore, we suggested that long-term exposure to low-dose of AgNPs could enhance malignant cell transformation in non-tumorigenic BEAS-2B cells. Our findings provide useful information needed to assess the carcinogenic potential of AgNPs.
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
Wun Hak
WH
Choo
Department of Nanofusion Technology, Hoseo University, Asan, Republic of Korea.
Cho Hee
CH
Park
Department of Nanofusion Technology, Hoseo University, Asan, Republic of Korea.
Shi Eun
SE
Jung
Department of Nanofusion Technology, Hoseo University, Asan, Republic of Korea.
Byeonghak
B
Moon
Department of Nanofusion Technology, Hoseo University, Asan, Republic of Korea.
Huiyeon
H
Ahn
Department of Nanofusion Technology, Hoseo University, Asan, Republic of Korea,; Croen Research Inc., Suwon, Republic of Korea.
Jung Seok
JS
Ryu
Department of Digital/System Control Engineering, Hoseo University, Asan, Republic of Korea.
Keun-Soo
KS
Kim
Department of Herbal Cosmetic Science, Hoseo University, Asan, Republic of Korea.
Yong Hwa
YH
Lee
Department of Nanofusion Technology, Hoseo University, Asan, Republic of Korea.
Il Je
IJ
Yu
Department of Nanofusion Technology, Hoseo University, Asan, Republic of Korea,. Electronic address: ohsm0403@hoseo.edu.
Seung Min
SM
Oh
D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007633:Keratins / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D053768:Metal Nanoparticles / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012834:Silver / Q000633:toxicity*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014746:Vimentin / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics
D015703:Antigens, CD; C494826:BAX protein, human; C513384:CDH1 protein, human; C050361:CDH2 protein, human; D015820:Cadherins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D016159:Tumor Suppressor Protein p53; D014746:Vimentin; D051028:bcl-2-Associated X Protein; D012834:Silver; D007633:Keratins; D053148:Caspase 3; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
Apoptosis; BEAS-2B cells; Chronic exposure; Malignant cell transformation; Metastasis; Silver nanoparticles