Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung

Yuanbin Chen, Melissa A. De Marco, Irene Graziani, Adi F. Gazdar, Peter R. Strack, Lucio Miele, Maurizio Bocchetta

Research output: Contribution to journalArticle

121 Scopus citations

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 γ-secretase cleavage product NIC-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 γ-secretase inhibitors or NOTCH-1 RNA interference. γ-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.

Original languageEnglish (US)
Pages (from-to)7954-7959
Number of pages6
JournalCancer research
Volume67
Issue number17
DOIs
StatePublished - Sep 1 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Chen, Y., De Marco, M. A., Graziani, I., Gazdar, A. F., Strack, P. R., Miele, L., & Bocchetta, M. (2007). Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung. Cancer research, 67(17), 7954-7959. https://doi.org/10.1158/0008-5472.CAN-07-1229