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The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.

Neutrophil elastase–mediated degradation of IRS-1 accelerates lung tumor growth

Open access
Houghton, A McGarry, Rzymkiewicz, Danuta M, Ji, Hongbin, Gregory, Alyssa D, Egea, Eduardo E, Metz, Heather E, Stolz, Donna B, Land, Stephanie R, Marconcini, Luiz A, Kliment, Corrine R, Jenkins, Kimberly M, Beaulieu, Keith A, Mouded, Majd, Frank, Stuart J, Wong, Kwok K, Shapiro, Steven D·2010·Nature Medicine
DOI 10.1038/nm.2084
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Abstract

Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that tumor-associated inflammatory cells may modify lung tumor growth and invasiveness. To determine the role of neutrophil elastase (encoded by Elane) on tumor progression, we used the loxP-Stop-loxP K-rasG12D (LSL–K-ras) model of mouse lung adenocarcinoma to generate LSL–K-ras-Elane−/− mice. Tumor burden was markedly reduced in LSL–K-ras-Elane−/− mice at all time points after induction of mutant K-ras expression. Kaplan-Meier survival analysis showed that whereas all LSL–K-ras-Elane+/+ mice died, none of the mice lacking neutrophil elastase died. Neutrophil elastase directly induced tumor cell proliferation in both human and mouse lung adenocarcinomas by gaining access to an endosomal compartment within tumor cells, where it degraded insulin receptor substrate-1 (IRS-1). Immunoprecipitation studies showed that, as neutrophil elastase degraded IRS-1, there was increased interaction between phosphatidylinositol 3-kinase (PI3K) and the potent mitogen platelet-derived growth factor receptor (PDGFR), thereby skewing the PI3K axis toward tumor cell proliferation. The inverse relationship identified between neutrophil elastase and IRS-1 in LSL–K-ras mice was also identified in human lung adenocarcinomas, thus translating these findings to human disease. This study identifies IRS-1 as a key regulator of PI3K within malignant cells. Additionally, to our knowledge, this is the first description of a secreted proteinase gaining access to the inside of a cell and altering intracellular signaling.

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Metadata

Authors
Houghton, A. M., Rzymkiewicz, D. M., Ji, H., Gregory, A. D., Egea, E. E., Metz, H. E., Stolz, D. B., Land, S. R., Marconcini, L. A., Kliment, C. R., Jenkins, K. M., Beaulieu, K. A., Mouded, M., Frank, S. J., Wong, K. K., & Shapiro, S. D.
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2010-01-17
Volume
16
Issue
2
Pages
219-223
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.2084
OpenAlex
W2098888044
Cited by
744
References
35
FWCI
7.50
Type
journal article
Language
en
Open access
green

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