Dominant-Negative Notch3 Receptor Inhibits Mitogen-Activated Protein Kinase Pathway and the Growth of Human Lung Cancers

Abstract

Notch3 is a member of an evolutionarily conserved family of cell surface receptors important in cell-fate determination in both vertebrates and invertebrates. Significant data support the role of Notch pathway in cancer development, although the conflicting role of Notch signaling pathways in tumorigenesis suggests that its action is highly context-dependent. Furthermore, although Notch receptors signal primarily through the regulation of hairy enhancer of split (HES) and HES-related (HRT) genes, they are known to crosstalk with other signaling pathways, including the epidermal growth factor (EGF) and the mitogen-activated protein kinase pathways. Whereas much is known about the role of Notch1 in human cancer, the role of Notch3 in epithelial tumors, such as lung carcinomas, has not been well established. In this study, we show that Notch3 is expressed in 80 of 207 (39%) resected human lung tumors and that its expression is positively correlated with EGF receptor expression. Inhibition of the Notch3 pathway using a dominant-negative receptor dramatically reduces growth in soft agar and increases growth factor dependence. We also find that Notch inhibition increases sensitivity to EGF receptor tyrosine kinase inhibition and decrease in phosphorylation of the mitogen-activated protein kinase. These observations support a role for Notch3 signaling in lung cancer, and one potential mechanism of maintaining the neoplastic phenotype is through the modulation of the EGF pathway. (Cancer Res 2005; 65(9): 3555-61)

Cross-talk between endothelial cells and tumor via delta-like ligand4/Notch/PTEN signaling inhibits lung cancer growth

“…Notch3 was reported to be overexpressed in about 40% of NSCLC, and its chromosomal translocation has been detected in certain lung cancer tissue, suggesting that Notch3 could be an oncogene in NSCLC (Haruki et al, 2005). Previous studies also documented that Notch1 was frequently expressed in lung cancer and correlated with the malignancy of NSCLC (Collins et al, 2004).…”

“…Aberrant expression of Notch in NSCLC has been illustrated in various studies (Collins et al, 2004;Haruki et al, 2005;Kunnimalaiyaan and Chen, 2007). Notch3 was reported to be overexpressed in about 40% of NSCLC, and its chromosomal translocation has been detected in certain lung cancer tissue, suggesting that Notch3 could be an oncogene in NSCLC (Haruki et al, 2005).…”

“…Accumulating evidence has revealed the aberrant expression of Notch components including Notch1, Notch3 and HES1 in NSCLC. However, the role of Notch in lung cancer development remains elusive (Collins et al, 2004;Haruki et al, 2005;Chen et al, 2007).…”

The lymphovascular embolus of inflammatory breast cancer exhibits a Notch 3 addiction

“…The therapeutic efficacy of notch inhibitors has been observed in other human cancer cell lines (Haruki et al, 2005;Park et al, 2006). Although pharmacological therapy with GSI-I was very effective in vitro, it was less effective in vivo, probably because of diffusion-limited effects of either tissue solubility or half-life.…”

Apoptosis, Oxidative Stress and Neurological Disease

“…Recent studies have shown that Notch3 signalling in VSMC plays an important role in down-regulating Fas-Ligand (FasL)-induced apoptosis (extrinsic apoptotic pathway) (30). Involvement of Notch3 in the regulation of apoptosis has also been observed in other cell types, such as lung carcinoma cells, where inhibition of the Notch3 signalling pathway mitigates the neoplastic phenotype (31). Finally, Viswanathan et al (2006) found widespread neuronal apoptosis in the cerebral cortex of CADASIL brains, demonstrating that the degree of neuronal apoptosis is related to the underlying subcortical white matter damage (32).…”