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

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-1IC, 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.

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Acknowledgements

We thank Patricia Simms for help with FACS analyses. Merck & CO., Inc. (Whitehouse Station, NJ, USA) kindly provided the MRK-003 compound. We thank Dr Michele Carbone for critical review of this paper. This work was supported by grants from the American Cancer Society RSG-05-077-MBC, Award Number RO1 CA134503 from the National Cancer Institute and by a grant from the Riviera Country Club and Sport Center. Financial support was from American Cancer Society grant RSG-05-077-MBC, Award Number RO1 CA134503 from the National Cancer Institute and by a grant by the Riviera Country Club and Sport Center (M Bocchetta). Merck Inc. provided the drug MRK-003.

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Eliasz, S., Liang, S., Chen, Y. et al. Notch-1 stimulates survival of lung adenocarcinoma cells during hypoxia by activating the IGF-1R pathway. Oncogene 29, 2488–2498 (2010). https://doi.org/10.1038/onc.2010.7

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