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

Abstract

Summary Lung cancer is the leading cause of cancer death worldwide1. Recent data suggest that tumor-associated inflammatory cells may modify lung tumor growth and invasiveness2-3. To determine the role of neutrophil elastase (NE or Elane) on tumor progression, we utilized the LSL-K-ras model of murine lung adenocarcinoma4 to generate LSL-K-ras/Elane−/− mice. Tumor burden was markedly reduced in LSL-K-ras/Elane−/− mice at all time points following induction of mutant K-ras expression. Kaplan-Meier life survival analysis demonstrated that while 100% of LSL-K-ras/Elane+/+ mice died, none of the mice lacking NE died. NE 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 (IRS1). Co-immunoprecipitation studies showed that as NE degraded IRS1, there was increased interaction between 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 NE and IRS1 in LSL-K-ras mice was also identified in human lung adenocarcinomas, thus translating these findings to human disease. This study identifies IRS1 as a key regulator of PI3K within malignant cells. Additionally, this is the first description of a secreted proteinase gaining access to a cell beyond its plasma membrane and altering intracellular signaling.

High‐fat diet protects the blood–brain barrier in an Alzheimer's disease mouse model

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Impact of chemotherapy-induced neutropenia on survival in patients with breast, ovarian and cervical cancer: a systematic review

“…Kowanetz et al described the accumulation of Ly6G+Ly6C+granulocytes in premetastaic tissues, facilitating colonization by cancer cells [30] . Furthermore, neutrophil elastase was shown to directly stimulate tumor cell proliferation in human and mouse lung adenocarcinomas [31] . This direct pro-tumoral role of neutrophils was also illustrated in elegant studies describing the impact of neutrophil associated matrix metalloprotease type 9 (MMP-9) on angiogenesis and early carcinogenesis [32] .…”

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