Clathrin Pit-mediated Endocytosis of Neutrophil Elastase and Cathepsin G by Cancer Cells

Gregory, Alyssa D.; Hale, Pamela; Perlmutter, David H.; Houghton, A. McGarry

doi:10.1074/jbc.m112.385617

Cited by 48 publications

(58 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In that study, we were also able to show that NE entered tumor cells, which resulted in the elimination of intracellular IRS-1. Since the time of that report, NE has been shown to enter multiple different cancer cell types, including breast cancer (30,31). NE also enters nonmalignant cells, such as fibroblasts (32) and hepatocytes (33), both of which caused the loss of intracellular IRS-1.…”

Section: Discussionmentioning

confidence: 99%

Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma

Metz

Kargl

Busch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Insulin receptor substrate-1 (IRS-1) is a signaling adaptor protein that interfaces with many pathways activated in lung cancer. It has been assumed that IRS-1 promotes tumor growth through its ability to activate PI3K signaling downstream of the insulin-like growth factor receptor. Surprisingly, tumors with reduced IRS-1 staining in a human lung adenocarcinoma tissue microarray displayed a significant survival disadvantage, especially within the Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant subgroup. Accordingly, adenoviral Cre recombinase (AdCre)-treated LSL-Kras/Irs-1fl/fl (Kras/Irs-1−/−) mice displayed increased tumor burden and mortality compared with controls. Mechanistically, IRS-1 deficiency promotes Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling via the IL-22 receptor, resulting in enhanced tumor-promoting inflammation. Treatment of Kras/Irs-1+/+ and Kras/Irs-1−/− mice with JAK inhibitors significantly reduced tumor burden, most notably in the IRS-1-deficient group.

show abstract

Section: Discussionmentioning

confidence: 99%

Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma

Metz

Kargl

Busch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…A recent study in lung cancer cells demonstrated that HNE and CG enter these cancer cells using a clathrin-and dynamindependent pathway and a caveolin-independent pathway. 27 Further studies are needed to characterize NSP uptake mechanisms in ECs.…”

Section: Anca-stimulated Neutrophils Release Active Nsps That Disruptmentioning

confidence: 99%

Neutrophil serine proteases exert proteolytic activity on endothelial cells

Jerke

Hernández²,

Beaudette³

et al. 2015

Kidney International

View full text Add to dashboard Cite

Neutrophil serine proteases (NSPs) are released from activated neutrophils during inflammation. Here we studied the transfer of the three major NSPs, namely proteinase 3, human neutrophil elastase, and cathepsin G, from neutrophils to endothelial cells and used an unbiased approach to identify novel endothelial NSP substrates. Enzymatically active NSPs were released from stimulated neutrophils and internalized by endothelial cells in a dose- and time-dependent manner as shown by immunoblotting, flow cytometry, and the Boc-Ala substrate assay. Using terminal-amine isotopic labeling of substrates in endothelial cells, we identified 121 peptides from 82 different proteins consisting of 36 substrates for proteinase 3, 30 for neutrophil elastase, and 28 for cathepsin G, respectively. We characterized the extended cleavage pattern and provide corresponding IceLogos. Gene ontology analysis showed significant cytoskeletal substrate enrichment and confirmed several cytoskeletal protein substrates by immunoblotting. Finally, ANCA-stimulated neutrophils released all three active NSPs into the supernatant. Supernatants increased endothelial albumin flux and disturbed the endothelial cell cytoskeletal architecture. Serine protease inhibition abrogated this effect. Longer exposure to NSPs reduced endothelial cell viability and increased apoptosis. Thus, we identified novel NSP substrates and suggest NSP inhibition as a therapeutic measure to inhibit neutrophil-mediated inflammatory vascular diseases.

show abstract

“…NE has been shown to have downstream effects on tumor cell proliferation and migration via extracellular mechanisms [21]. Alternatively, published reports and our data have shown uptake-dependent effects of NE on tumor cell proliferation and antigen presentation [5, 8, 22]. Thus, it is important to delineate whether NE uptake was required for its regulation of HLA class I.…”

Section: Resultsmentioning

confidence: 75%

“…Thus, it is important to delineate whether NE uptake was required for its regulation of HLA class I. To investigate this, we used CPZ, which inhibits clathrin-coated pit-mediated endocytosis [23, 24], which was shown to play a role in NE uptake by solid tumors [22]. MDA-MB-231 cells were treated with CPZ prior to culture in NE-supplemented media for 8 hours.…”

Section: Resultsmentioning

confidence: 99%

“…For example, while Erluslanov et al showed that TAN produce proinflammatory cytokines and costimulatory molecules that enhanced anti-tumoral T cell responses in lung cancer [2], Houghton et al showed that the uptake of NE by solid tumors, including lung cancer, leads to degradation of insulin receptor substrate-1 in tumor cells, which activates the phosphoinositide 3-kinase pathway ultimately promoting tumor cell proliferation [5, 22]. Although our work does not provide an explanation for the dichotomous reports where inflammation is beneficial in some tumors and deleterious in others, our report, along with previous studies, highlights the importance of individual components of the tumor inflammatory microenvironment that could be targeted to enhance (or attenuate) the anti-tumoral (or pro-tumoral) immune effects.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Neutrophil elastase enhances antigen presentation by upregulating human leukocyte antigen class I expression on tumor cells

Chawla

Alatrash

Philips

et al. 2016

Cancer Immunol Immunother

View full text Add to dashboard Cite

Neutrophil elastase (NE) is an innate immune cell-derived inflammatory mediator that we have shown increases the presentation of tumor-associated peptide antigens in breast cancer. In this study, we extend these observations to show that NE uptake has a broad effect on enhancing antigen presentation by breast cancer cells. We show that NE increases human leukocyte antigen (HLA) class I expression on the surface of breast cancer cells in a concentration and time-dependent manner. HLA class I upregulation requires internalization of enzymatically active NE. Western blots of NE-treated breast cancer cells confirm that the expression of total HLA class I as well as the antigen processing machinery proteins TAP1, LMP2, and calnexin do not change following NE treatment. This suggests that NE does not increase the efficiency of antigen processing; rather it mediates the upregulation of HLA class I by stabilizing and reducing membrane recycling of HLA class I molecules. Furthermore, the effects of NE extend beyond breast cancer since the uptake of NE by EBV-LCL increases the presentation of HLA class I-restricted viral peptides, as shown by their increased sensitivity to lysis by EBV-specific CD8+ T cells. Together, our results show that NE uptake increases the responsiveness of breast cancer cells to adaptive immunity by broad upregulation of membrane HLA class I, and support the conclusion that the innate inflammatory mediator NE enhances tumor cell recognition and increases tumor sensitivity to the host adaptive immune response.

show abstract

Clathrin Pit-mediated Endocytosis of Neutrophil Elastase and Cathepsin G by Cancer Cells

Cited by 48 publications

References 30 publications

Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma

Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma

Neutrophil serine proteases exert proteolytic activity on endothelial cells

Neutrophil elastase enhances antigen presentation by upregulating human leukocyte antigen class I expression on tumor cells

Contact Info

Product

Resources

About