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 (CdCl) 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 CdCl 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 CdCl-induced EMT, stress fiber formation, high cell motility, and antitumor drug resistance. In addition, we found that prolonged CdCl 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-1α, and IGF-1R/Akt/ERK/S6K1 activated each other to induce EMT in the CdCl-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.

lncRNA FAM83H‑AS1 is associated with the prognosis of colorectal carcinoma and promotes cell proliferation by targeting the Notch signaling pathway

“…Furthermore, concomitant upregulation of two Notch signaling molecules, Notch1 and Hes1, was obtained in both CRC tissues and cell lines, indicating the potential mechanism of FAM83H-AS1/Notch signal pathway in CRC. Notch signaling pathway has been reported to involve in the tumorigenesis of various cancer types (23,32,33). In our study, we showed the accompanied activation of Notch signaling in CRC tissues and cells and rescue assays revealed that the growth inhibition mediated by the knockdown of FAM83H-AS1 was at least in a Notch signal dependent manner, which was further confirmed by the effect of DAPT on Notch1 and FAM83H-AS1 as well as the unchanged cell proliferation after Notch1 was silenced by DAPT.…”

Crosstalk between Notch, HIF-1α and GPER in Breast Cancer EMT

“…Snail has been shown to repress E-cadherin expression by recruiting histone-modifying enzymes at the CDH1 gene promoter (coding E-cadherin protein), including Sin3A-HDAC1/2 [ 53 ], Polycomb complex 2 (PRC2) [ 54 ] or Lysisn-specific demethylase 1 (LSD1) [ 55 ], which turn chromatin into an inactive state. In different types of cancer cells, Notch signaling promotes EMT by directly inducing Snail expression [ 6 , 38 , 56 , 57 ]. At transcriptional level, Notch regulates Snail expression through the tripartite complex NICD-CSL-MAML-1, as demonstrated by the evidence that the dominant-negative mutant of MAML-1 (DN-MAML-1) inhibits Snail expression and EMT in cancer cells [ 6 , 38 ].…”

“…In line with this model, the aforementioned study showed that inhibition of either γ-secretase activity or a transcriptional coactivator of Notch-NICD prevents the invasiveness of breast cancer cells [ 98 ]. The non-transcriptional role of HIF-1α in the activation of Notch signaling was further confirmed in lung adenocarcinoma cancer cells, where cadmium exposure was shown to induce EMT by Notch-dependent expression of Snail, in a HIF-1α dependent manner [ 57 ].…”

The role of developmental signaling pathways in non-small cell lung carcinoma

“…Notch-1 has also been implicated in the acquisition of resistance to gefitinib and in EMT induction in tumors; antagonizing the receptor with either short hairpin (shRNA) or a γ-secretase inhibitor (GSI) reversed the observed effects [58]. Furthermore, prolonged cadmium exposure upregulated Notch-1 levels and conferred cisplatin resistance upon the AC cell line H1975 [59]. Along this vein, the role of Notch-2 in NSCLC progression is ambiguous based on recent evidence.…”