Involvement of Notch1 signaling in malignant progression of A549 cells subjected to prolonged cadmium exposure

被引:37
作者
Fujiki, Kota [1 ]
Inamura, Hisako [1 ]
Miyayama, Takamitsu [1 ]
Matsuoka, Masato [1 ]
机构
[1] Tokyo Womens Med Univ, Dept Hyg & Publ Hlth 1, Tokyo 1628666, Japan
基金
日本学术振兴会;
关键词
EPITHELIAL-MESENCHYMAL TRANSITION; GAMMA-SECRETASE; BREAST-CANCER; PROLIFERATION; RECEPTOR; ACTIVATION; EXPRESSION; APOPTOSIS; INSIGHTS; PATHWAYS;
D O I
10.1074/jbc.M116.759134
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 1 alpha (HIF-1 alpha), 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 mu M 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 CdCl2 exposure 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 CdCl2 exposure 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-1 alpha, 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-1 alpha and IGF-1R/Akt/ERK/S6K1 signaling pathways, promotes malignant progression stimulated by prolonged cadmium exposure in this lung adenocarcinoma model.
引用
收藏
页码:7942 / 7953
页数:12
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