Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth.
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-ras(G12D) (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.
Houghton
A McGarry
AM
Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Rzymkiewicz
Danuta M
DM
Ji
Hongbin
H
Gregory
Alyssa D
AD
Egea
Eduardo E
EE
Metz
Heather E
HE
Stolz
Donna B
DB
Land
Stephanie R
SR
Marconcini
Luiz A
LA
Kliment
Corrine R
CR
Jenkins
Kimberly M
KM
Beaulieu
Keith A
KA
Mouded
Majd
M
Frank
Stuart J
SJ
Wong
Kwok K
KK
Shapiro
Steven D
SD
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002460:Cell Line; D006801:Humans; D006868:Hydrolysis; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D019272:Leukocyte Elastase / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice
D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D019272:Leukocyte Elastase