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.