Oxygen Concentration Determines the Biological Effects of NOTCH-1 Signaling in Adenocarcinoma of the Lung

Abstract

NOTCH signaling is an evolutionarily conserved signaling pathway that regulates cell fate during development and postnatal life. It has been increasingly linked to carcinogenesis, although its role in cancer seems to be highly context and tissue specific. Although NOTCH signaling is required for lung development, little is known about its role in lung cancer. In this study, we show that NOTCH signaling, as measured by the ;-secretase cleavage product N IC -1, is active in both normal human and lung tumor samples; however, downstream NOTCH readouts (i.e., HES-1 and HES-5) are elevated in lung tumors. Levels of NOTCH signaling components in primary human lung cells reflect observations in tissue samples, yet lung tumor cell lines showed little NOTCH signaling. Because oxygen concentrations are important in normal lung physiology and lung tumors are hypoxic, the effect of low oxygen on these lung tumor cell lines was evaluated. We found that hypoxia dramatically elevates NOTCH signaling (especially NOTCH-1) in lung tumor cell lines and concomitantly sensitizes them to inhibition via small-molecule ;-secretase inhibitors or NOTCH-1 RNA interference. ;-Secretase inhibitorinduced apoptosis of lung tumor cells grown under hypoxic conditions could be rescued by reintroduction of active NOTCH-1. Our data strengthen the role of NOTCH in lung cancer and as a therapeutic target for the treatment of lung and other hypoxic tumor types. [Cancer Res 2007;67(17):7954-9]

Amyloid Precursor Protein (APP) Affects Global Protein Synthesis in Dividing Human Cells

“…APP appeared to be actively cleaved in NSCLC cells, as GSI treatment led to a dose‐dependent accumulation of total APP (Fig. 2D), similar to what was observed for Notch‐1 in the same cells (Chen et al, 2007). Further examination of the overall 4E‐BP1 phosphorylation status after APP downregulation revealed decreased phosphorylation at S65 and unchanged phosphorylation at T70 (Fig.…”

“…In previous studies, we targeted hypoxic tumor tissue in experimental, orthotopic NSCLC models using γ‐secretase inhibitors in order to inhibit Notch‐1 signaling (Chen et al, 2007; Eliasz et al, 2010; Liang et al, 2012). γ‐secretase treatment proved effective in specifically killing hypoxic NSCLC, reducing its overall volume, increasing median survival, and reducing expression of hypoxia markers in NSCLC biopsies (Liang et al, 2012).…”

“…In several solid tumors, including NSCLC, hypoxic tissues require Notch signaling for survival or for hypoxia‐induced proliferation (Chen et al, 2007; Eliasz et al, 2010; Xing et al, 2011; Zou et al, 2013). In a previous study we found that Notch inhibition through administration of γ‐secretase inhibitors (GSI) can target hypoxic NSCLC specifically, thus reducing its volume and related markers in an orthotopic NSCLC model (Liang et al, 2012).…”

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

“…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).…”

Differential expression of the Notch1 receptor, and its ligands Dll1, Dll3 and Dll4 in distinct human pituitary adenoma subtypes

“…Notch1 serves a promoting role in the majority of carcinoma types, but serves an antitumor role in skin, lung, liver, thyroid and breast cancer. Notch1 has a promoting effect in the early stage of cervical cancer, while inhibiting tumor growth in end-stage cervical cancer (25). A possible explanation for the differences in Notch1 function may be that it is highly conserved during biological evolution and expressed in various tissues and cells.…”