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 gamma-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 gamma-secretase inhibitors or NOTCH-1 RNA interference. gamma-Secretase inhibitor-induced 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.
Highlights
Lung cancers are the most common malignancies in the United States, accounting for 31% of male and 26% of female cancerrelated deaths (1)
The seven Adenocarcinoma of the lung (ACL) lines displayed reduced or undetectable amounts of NOTCH-1 (Fig. 1A), with similar observations made at the mRNA level (Fig. 1C)
We compared NOTCH-1 expression levels in one ACL cell line and in one SA culture grown in RPMI 1640 and the media used for primary cells
Summary
Lung cancers are the most common malignancies in the United States, accounting for 31% of male and 26% of female cancerrelated deaths (1). We have studied the expression levels and the biological effects of NOTCH signaling in ACL using cell lines and frozen tumor biopsies. We measured the expression levels of the four NOTCH receptors and ligands JAGGED-1 and DELTA-1 and DELTA-4 in 10 NSCLC cell lines compared with primary bronchoepithelial, small airway epithelial, and lung fibroblast by Western blot (Fig. 1A and B).
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