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

被引：133

作者：

Eliasz, S. ^{[1
]}

Liang, S. ^{[1
]}

Chen, Y. ^{[2
]}

De Marco, M. A. ^{[1
]}

Machek, O. ^{[1
]}

Skucha, S. ^{[1
]}

Miele, L. ^{[3
]}

Bocchetta, M. ^{[1
]}

机构：

[1] Loyola Univ Chicago, Cardinal Bernardin Canc Ctr, Inst Oncol, 2160 S 1st Ave,Bldg 112,Room 204, Maywood, IL 60153 USA

[2] NYU, Dept Surg, Langone Med Ctr, New York, NY 10016 USA

[3] Univ Mississippi, Med Ctr, Inst Canc, Jackson, MS 39216 USA

来源：

ONCOGENE | 2010年 / 29卷 / 17期

关键词：

notch signaling; lung cancer; hypoxia; IGF-1R; cancer cell survival; CANCER STEM-CELLS; FACTOR-I GENE; PROTEIN-KINASE; GROWTH; INSULIN; EXPRESSION; TRANSCRIPTION; RESISTANCE; MAINTENANCE; INHIBITION;

D O I：

10.1038/onc.2010.7

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 ifically 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 c-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. Oncogene (2010) 29, 2488-2498; doi:10.1038/onc.2010.7; published online 15 February 2010

引用

页码：2488 / 2498

页数：11