Notch-1 stimulates survival of lung adenocarcinoma cells during hypoxia by activating the IGF-1R pathway

S. Eliasz, S. Liang, Y. Chen, M. A. De Marco, O. MacHek, S. Skucha, L. Miele, M. Bocchetta

Research output: Contribution to journalArticlepeer-review

122 Scopus citations

Abstract

Hypoxic microenvironment supports cancer stem cell survival, causes poor response to anticancer therapy and tumor recurrence. Inhibition of Notch-1 signaling in adenocarcinoma of the lung (ACL) cells causes apoptosis specifically under hypoxia. Here, we found that Akt-1 activation is a key mediator of Notch-1 pro-survival effects under hypoxia. Notch-1 activates Akt-1 through repression of phosphatase and tensin (PTEN) homolog expression and induction of the insulin-like growth factor 1 receptor (IGF-1R). The latter seems to be the major determinant of Akt-1 stimulation, as Notch-1 signaling affects Akt-1 activation in PTEN/ACL cells. Both downregulation of insulin receptor substrate 1 (IRS-1) and dominant-negative IGF-1R sensitized ACL cells to γ-secretase inhibitor (GSI)-induced apoptosis. Conversely, overexpression of IGF-1R protected ACL cells from GSI toxicity. Inhibition of Notch-1 caused reduced IGF-1R expression, whereas forced Notch-1 expression yielded opposite effects. Chromatin immunoprecipitation experiments suggested Notch-1 direct regulation of the IGF-1R promoter. Experiments in which human ACL cells were injected in mice confirmed elevated and specific co-expression of Notch-1 IC, IGF-1R and pAkt-1 in hypoxic tumor areas. Our data provide a mechanistic explanation for Notch-1-mediated pro-survival function in hypoxic ACL tumor microenvironment. The results identify additional targets that may synergize with Notch-1 inhibition for ACL treatment.

Original languageEnglish (US)
Pages (from-to)2488-2498
Number of pages11
JournalOncogene
Volume29
Issue number17
DOIs
StatePublished - Apr 2010
Externally publishedYes

Keywords

  • Cancer cell survival
  • Hypoxia
  • IGF-1R
  • Lung cancer
  • Notch signaling

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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