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.
Similar content being viewed by others
References
Adams TE, Epa VC, Garrett TP, Ward CW . (2000). Structure and function of the type 1 insulin-like growth factor receptor. Cell Mol Life Sci 57: 1050–1093.
Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB et al. (1997). Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7: 261–269.
Artavanis-Tsakonas S, Rand MD, Lake RJ . (1999). Notch signaling: cell fate control and signal integration in development. Science 284: 770–776.
Baserga R, Hongo A, Rubini M, Prisco M, Valentinis B . (1997). The IGF-I receptor in cell growth, transformation and apoptosis. Biochim Biophys Acta 1332: F105–F126.
Behrooz A, Ismail-Beigi F . (1999). Stimulation of glucose transport by hypoxia: signals and mechanisms. News Physiol Sci 14: 105–110.
Belfiore A . (2007). The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer. Curr Pharm Des 13: 671–686.
Bendall SC, Stewart MH, Menendez P, George D, Vijayaragavan K, Werbowetski-Ogilvie T et al. (2007). IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro. Nature 448: 1015–1021.
Bocchetta M, Eliasz S, De Marco MA, Rudzinski J, Zhang L, Carbone M . (2008). The SV40 large T antigen-p53 complexes bind and activate the insulin-like growth factor-I promoter stimulating cell growth. Cancer Res 68: 1022–1029.
Carelli S, Di Giulio AM, Paratore S, Bosari S, Gorio A . (2006). Degradation of insulin-like growth factor-I receptor occurs via ubiquitin-proteasome pathway in human lung cancer cells. J Cell Physiol 208: 354–362.
Chen DL, Dehdashti F . (2005). Advances in positron emission tomographic imaging of lung cancer. Proc Am Thorac Soc 2: 541–544.
Chen WS, Xu PZ, Gottlob K, Chen ML, Sokol K, Shiyanova T et al. (2001). Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev 15: 2203–2208.
Chen Y, De Marco MA, Graziani I, Gazdar AF, Strack PR, Miele L et al. (2007). Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung. Cancer Res 67: 7954–7959.
Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw III EB et al. (2001a). Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292: 1728–1731.
Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ . (2001b). Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 276: 38349–38352.
Dang TP, Gazdar AF, Virmani AK, Sepetavec T, Hande KR, Minna JD et al. (2000). Chromosome 19 translocation, overexpression of Notch3, and human lung cancer. J Natl Cancer Inst 92: 1355–1357.
Ebert BL, Firth JD, Ratcliffe PJ . (1995). Hypoxia and mitochondrial inhibitors regulate expression of glucose transporter-1 via distinct Cis-acting sequences. J Biol Chem 270: 29083–29089.
Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS . (2009). Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15: 232–239.
Frasca F, Pandini G, Sciacca L, Pezzino V, Squatrito S, Belfiore A et al. (2008). The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch Physiol Biochem 114: 23–37.
Fryer CJ, Lamar E, Turbachova I, Kintner C, Jones KA . (2002). Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex. Genes Dev 16: 1397–1411.
Graziani I, Eliasz S, De Marco MA, Chen Y, Pass HI, De May RM et al. (2008). Opposite effects of Notch-1 and Notch-2 on mesothelioma cell survival under hypoxia are exerted through the Akt pathway. Cancer Res 68: 9678–9685.
Guo A, Villén J, Kornhauser J, Lee KA, Stokes MP, Rikova K et al. (2008). Signaling networks assembled by oncogenic EGFR and c-Met. Proc Natl Acad Sci USA 105: 692–697.
Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J et al. (2005). Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 9: 617–628.
Haruki N, Kawaguchi KS, Eichenberger S, Massion PP, Olson S, Gonzalez A et al. (2005). Dominant-negative Notch3 receptor inhibits mitogen-activated protein kinase pathway and the growth of human lung cancers. Cancer Res 65: 3555–3561.
Heuson JC, Legros N . (1972). Influence of insulin deprivation on growth of the 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats subjected to alloxan diabetes and food restriction. Cancer Res 32: 226–232.
Keith B, Simon MC . (2007). Hypoxia-inducible factors, stem cells, and cancer. Cell 129: 465–472.
Klinakis A, Szabolcs M, Politi K, Kiaris H, Artavanis-Tsakonas S, Efstratiadis A . (2006). Myc is a Notch1 transcriptional target and a requisite for Notch1-induced mammary tumorigenesis in mice. Proc Natl Acad Sci USA 103: 9262–9267.
Konishi J, Kawaguchi KS, Vo H, Haruki N, Gonzalez A, Carbone DP et al. (2007). Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers. Cancer Res 67: 8051–8057.
Korkaya H, Wicha MS . (2009). HER-2, notch, and breast cancer stem cells: targeting an axis of evil. Clin Cancer Res 15: 1845–1847.
Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ et al. (2005). Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105: 659–669.
McLellan AS, Kealey T, Langlands K . (2006). An E box in the exon 1 promoter regulates insulin-like growth factor-I expression in differentiating muscle cells. Am J Physiol Cell Physiol 291: C300–C307.
Miele L, Golde T, Osborne B . (2006). Notch signaling in cancer. Curr Mol Med 6: 905–918.
Milas L, Hittelman WN . (2009). Cancer stem cells and tumor response to therapy: current problems and future prospects. Semin Radiat Oncol 19: 96–105.
Moromisato DY, Moromisato MY, Zanconato S, Roberts Jr CT . (1996). Effect of hypoxia on lung, heart, and liver insulin-like growth factor-I gene and receptor expression in the newborn rat. Crit Care Med 24: 919–924.
Nam Y, Sliz P, Song L, Aster JC, Blacklow SC . (2006). Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell 124: 973–983.
Ouellet J, Li S, Roy R . (2008). Notch signalling is required for both dauer maintenance and recovery in C. elegans. Development 135: 2583–2592.
Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F et al. (2009). Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15: 220–231.
Palomero T, Lim WK, Odom DT, Sulis ML, Real PJ, Margolin A et al. (2006). NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci USA 103: 18261–18266.
Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M et al. (2007). Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 13: 1203–1210.
Pollak M . (2008). Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8: 915–928.
Romanelli RJ, LeBeau AP, Fulmer CG, Lazzarino DA, Hochberg A, Wood TL . (2007). Insulin-like growth factor type-I receptor internalization and recycling mediate the sustained phosphorylation of Akt. J Biol Chem 282: 22513–22524.
Ruggero D, Pandolfi PP . (2003). Does the ribosome translate cancer? Nat Rev Cancer 3: 179–192.
Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U . (2008). Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA 105: 6392–6397.
Schuurbiers OC, Kaanders JH, van der Heijden HF, Dekhuijzen RP, Oyen WJ, Bussink J . (2009). The PI3-K/AKT-pathway and radiation resistance mechanisms in non-small cell lung cancer. J Thorac Oncol 4: 761–767.
Sell C, Dumenil G, Deveaud C, Miura M, Coppola D, DeAngelis T et al. (1994). Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts. Mol Cell Biol 14: 3604–3612.
Shemer J, Adamo ML, Roberts Jr CT, LeRoith D . (1992). Tissue-specific transcription start site usage in the leader exons of the rat insulin-like growth factor-I gene: evidence for differential regulation in the developing kidney. Endocrinology 131: 2793–2799.
Swiatek PJ, Lindsell CE, del Amo FF, Weinmaster G, Gridley T . (1994). Notch1 is essential for postimplantation development in mice. Genes Dev 8: 707–719.
Treins C, Giorgetti-Peraldi S, Murdaca J, Monthouël-Kartmann MN, Van Obberghen E . (2005). Regulation of hypoxia-inducible factor (HIF)-1 activity and expression of HIF hydroxylases in response to insulin-like growth factor I. Mol Endocrinol 19: 1304–1317.
Tschopp O, Yang ZZ, Brodbeck D, Dummler BA, Hemmings-Mieszczak M, Watanabe T et al. (2005). Essential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis. Development 132: 2943–2954.
Venkateswaran V, Haddad AQ, Fleshner NE, Fan R, Sugar LM, Nam R . (2007). Association of diet-induced hyperinsulinemia with accelerated growth of prostate cancer (LNCaP) xenografts. J Natl Cancer Inst 99: 1793–1800.
Weng AP, Nam Y, Wolfe MS, Pear WS, Griffin JD, Blacklow SC et al. (2003). Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol 23: 655–664.
Yoyoshima Y, Monson C, Duan C, Wu Y, Gao C, Yakar S et al. (2008). The role of insulin receptor signaling in zebrafish embryogenesis. Endocrinology 149: 5996–6005.
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Oncogene website
Supplementary information
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2010.7
- Springer Nature Limited
Keywords
This article is cited by
-
LncRNAs LCETRL3 and LCETRL4 at chromosome 4q12 diminish EGFR-TKIs efficiency in NSCLC through stabilizing TDP43 and EIF2S1
Signal Transduction and Targeted Therapy (2022)
-
Targeting Notch in oncology: the path forward
Nature Reviews Drug Discovery (2021)
-
LncRNA SNHG15 regulates EGFR-TKI acquired resistance in lung adenocarcinoma through sponging miR-451 to upregulate MDR-1
Cell Death & Disease (2020)
-
Latest progress on the molecular mechanisms of idiopathic pulmonary fibrosis
Molecular Biology Reports (2020)
-
Relationship between the upregulation of Notch1 signaling and the clinical characteristics of patients with papillary thyroid carcinoma in East Asia: a systematic review and meta-analysis
Cancer Cell International (2019)