Neutrophil Elastase-Mediated Degradation of IRS-1 Accelerates Lung Tumor Growth

By A. M. Houghton, D. Rzymkiewicz, Hongbin Ji, A. Gregory, Eduardo E. Egea, H. Metz, D. Stolz, S. Land, Luiz A Marconcini, C. Kliment and 6 more. Nature Medicine, 2010

723 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/3cf6fe3388bf0b6e1d19025f81ce0e0fa4631a6f

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Citations in the corpus

The Multifaceted Functions of Neutrophils (2013, neutral): “F or p er so na l u se o nl y. • OH Fe2+ Azurophilic (primary) granules: myeloperoxidase, elastase, defensin, cathepsin G, proteinase 3, BPI, β-glucuronidase, iNOS NETs: Extracellular DNA with elastase, myeloperoxidase, and antimicrobial peptides Secondary and tertiary granules: Lactoferrin, MMP8, M”
Coordinated regulation of myeloid cells by tumours (2012, background): “Degradation of IRS1 facilitates interactions between phosphoinositide 3-kinase (PI3K) and the receptor for the mitogen platelet-derived growth factor (PDGF), thus promoting tumour cell proliferatio”
Diverse novel functions of neutrophils in immunity, inflammation, and beyond (2013, background): “…the intracellular space (endocytic compartments) of hepatocytes and degrades insulin receptor substrate 1 (IRS-1), leading to attenuation of insulin signal transduction pathways (Talukdar et al., 2012; similar to a mechanism previously proposed to occur in lung cancer cells; Houghton et al., 2010).”
Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases (2017, neutral): “Indeed, CXCR1/2 ligands played a significant role in neutrophil tumor infiltration that facilitated cancer cell proliferation, invasion, and chemoresistance via increased levels of angiogenic and growth factors produced by these tumor-associated neutrophils [125, 364-366].”
Roles of the immune system in cancer: from tumor initiation to metastatic progression (2018, background): “Also, neutrophil elastase acts as a potent elastolytic enzyme that, when secreted in a site of inflammation, promotes tumor cell invasion, angiogenesis, and cancer cell proliferation (Houghton et al. 2010; Gong et al. 2013).”
Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment (2016, background): “As neutrophil-derived molecules play critical roles in a wide range of stages of tumor progression [59], targeting neutrophil-secreted enzymes or cytokines could be another effective approach [100].”
Tumor-associated neutrophils: new targets for cancer therapy. (2011, methodology): “Studies in our laboratory have shown that treatment of LSL–K-ras tumor–bearing mice with the synthetic NE inhibitor ONO5046 reduced tumor growth by 3-fold (24).”
Tumor associated macrophages and neutrophils in cancer. (2013, background): “In addition, in models of subcutaneous melanoma or fibrosarcoma, ed in Tecchio et al. 2013). nce Pro-tumoral Reference NE Houghton et al. (2010) BAFF, APRIL Tecchio et al. (2013) HGF Wislez et al. (2003) TGF- Aoyagi et al. (2004) ella (2006) OSM Queen et al. (2005) o et al. (2013) HGF Wislez et al.…”
Neutrophils in the activation and regulation of innate and adaptive immunity (2011, background): “IRS1 binds to a subunit of phosphoinositide 3-kinase (PI3K) and blocks its interaction with the platelet-derived growth factor receptor (PDGFR”