title: Involvement of Notch1 signaling in malignant progression of A549 cells subjected to prolonged cadmium exposure.
abstract: Cadmium exposure is known to increase lung cancer risk, but the underlying molecular mechanisms in cadmium-stimulated progression of malignancy are unclear. Here, we examined the effects of prolonged cadmium exposure on the malignant progression of A549 human lung adenocarcinoma cells and the roles of Notch1, hypoxia-inducible factor 1α (HIF-1α), and insulin-like growth factor 1 receptor (IGF-1R)/Akt/extracellular signal-regulated kinase (ERK)/p70 S6 kinase 1 (S6K1) signaling pathways. Exposing A549 cells to 10 or 20 μm cadmium chloride (CdCl2) for 9-15 weeks induced a high proliferative potential, the epithelial-mesenchymal transition (EMT), stress fiber formation, high cell motility, and resistance to antitumor drugs. Of note, the CdCl2exposure increased the levels of the Notch1 intracellular domain and of the downstream Notch1 target genes Snail and Slug. Strikingly, siRNA-mediated Notch1 silencing partially suppressed the CdCl2-induced EMT, stress fiber formation, high cell motility, and antitumor drug resistance. In addition, we found that prolonged CdCl2exposure induced reduction of E-cadherin in BEAS-2B human bronchial epithelial cells and antitumor drug resistance in H1975 human tumor-derived non-small-cell lung cancer cells depending on Notch1 signaling. Moreover, Notch1, HIF-1α, and IGF-1R/Akt/ERK/S6K1 activated each other to induce EMT in the CdCl2-exposed A549 cells. These results suggest that Notch1, along with HIF-1α and IGF-1R/Akt/ERK/S6K1 signaling pathways, promotes malignant progression stimulated by prolonged cadmium exposure in this lung adenocarcinoma model.
authors.affiliation: From the Department of Hygiene and Public Health I, Tokyo Women's Medical University, Tokyo 162-8666, Japan bunnsidairoku@gmail.com.
authors.forename: Kota
authors.initials: K
authors.lastname: Fujiki
authors.affiliation: From the Department of Hygiene and Public Health I, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Inamura
authors.affiliation: From the Department of Hygiene and Public Health I, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Miyayama
authors.affiliation: From the Department of Hygiene and Public Health I, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D000072283:A549 Cells; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000737:chemistry; D001980:Bronchi / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D019256:Cadmium Chloride / Q000737:chemistry*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017526:Receptor, IGF Type 1; D051881:Receptor, Notch1 / Q000378:metabolism*; D017451:Receptors, Somatomedin / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C513384:CDH1 protein, human; D015820:Cadherins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000597236:IGF1R protein, human; C497761:NOTCH1 protein, human; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D017451:Receptors, Somatomedin; D017526:Receptor, IGF Type 1; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D048049:Extracellular Signal-Regulated MAP Kinases; D019256:Cadmium Chloride
keywords: Notch pathway; cadmium; drug resistance; epithelial-mesenchymal transition (EMT); lung cancer; metal