Notch-1 stimulates survival of lung adenocarcinoma cells during hypoxia by activating the IGF-1R pathway.
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 gamma-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.
Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153, USA.
S
S
Eliasz
S
S
Liang
Y
Y
Chen
M A
MA
De Marco
O
O
Machek
S
S
Skucha
L
L
Miele
M
M
Bocchetta
D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D051059:PTEN Phosphohydrolase / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D051881:Receptor, Notch1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase