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Korkmaz B, Lamort AS, Domain R, et al. Cathepsin C inhibition as a potential treatment strategy in cancer. Biochem Pharmacol. 2021;194:114803doi: 10.1016/j.bcp.2021.114803.
Korkmaz, B., Lamort, A. S., Domain, R., Beauvillain, C., Gieldon, A., Yildirim, A. �. �., Stathopoulos, G. T., Rhimi, M., Jenne, D. E., & Kettritz, R. (2021). Cathepsin C inhibition as a potential treatment strategy in cancer. Biochemical pharmacology, 194114803. https://doi.org/10.1016/j.bcp.2021.114803
Korkmaz, Brice, et al. "Cathepsin C inhibition as a potential treatment strategy in cancer." Biochemical pharmacology vol. 194 (2021): 114803. doi: https://doi.org/10.1016/j.bcp.2021.114803
Korkmaz B, Lamort AS, Domain R, Beauvillain C, Gieldon A, Yildirim AÖ, Stathopoulos GT, Rhimi M, Jenne DE, Kettritz R. Cathepsin C inhibition as a potential treatment strategy in cancer. Biochem Pharmacol. 2021 Dec;194:114803. doi: 10.1016/j.bcp.2021.114803. Epub 2021 Oct 20. PMID: 34678221.
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Biochem Pharmacol. 2021 Dec;194:114803. doi: 10.1016/j.bcp.2021.114803. Epub 2021 Oct 20.

Cathepsin C inhibition as a potential treatment strategy in cancer.

Biochemical pharmacology

Brice Korkmaz, Anne-Sophie Lamort, Roxane Domain, Céline Beauvillain, Artur Gieldon, Ali Önder Yildirim, Georgios T Stathopoulos, Moez Rhimi, Dieter E Jenne, Ralph Kettritz

Affiliations

  1. INSERM UMR-1100, "Research Center for Respiratory Diseases" and University of Tours, 37032 Tours, France. Electronic address: [email protected].
  2. Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), Helmholtz Center Munich-German Research Center for Environmental Health (HMGU) and Ludwig-Maximilian-University (LMU), Munich, Bavaria 81377, Germany(2).
  3. INSERM UMR-1100, "Research Center for Respiratory Diseases" and University of Tours, 37032 Tours, France.
  4. University of Angers, University of Nantes, Angers University Hospital, INSERM UMR-1232, CRCINA, Innate Immunity and Immunotherapy, SFR ICAT, 49000 Angers, France.
  5. Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland.
  6. Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, Jouy-en-Josas, France.
  7. Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), Helmholtz Center Munich-German Research Center for Environmental Health (HMGU) and Ludwig-Maximilian-University (LMU), Munich, Bavaria 81377, Germany(2); Max Planck Institute of Neurobiology, 82152 Planegg-Martinsried, Germany.
  8. Experimental and Clinical Research Center, Charité und Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft (MDC), Berlin, Germany; Nephrology and Intensive Care Medicine, Charité-Universitätsmedizin, Berlin, Germany.

PMID: 34678221 DOI: 10.1016/j.bcp.2021.114803

Abstract

Epidemiological studies established an association between chronic inflammation and higher risk of cancer. Inhibition of proteolytic enzymes represents a potential treatment strategy for cancer and prevention of cancer metastasis. Cathepsin C (CatC) is a highly conserved lysosomal cysteine dipeptidyl aminopeptidase required for the activation of pro-inflammatory neutrophil serine proteases (NSPs, elastase, proteinase 3, cathepsin G and NSP-4). NSPs are locally released by activated neutrophils in response to pathogens and non-infectious danger signals. Activated neutrophils also release neutrophil extracellular traps (NETs) that are decorated with several neutrophil proteins, including NSPs. NSPs are not only NETs constituents but also play a role in NET formation and release. Although immune cells harbor large amounts of CatC, additional cell sources for this protease exists. Upregulation of CatC expression was observed in different tissues during carcinogenesis and correlated with metastasis and poor patient survival. Recent mechanistic studies indicated an important interaction of tumor-associated CatC, NSPs, and NETs in cancer development and metastasis and suggested CatC as a therapeutic target in a several cancer types. Cancer cell-derived CatC promotes neutrophil recruitment in the inflammatory tumor microenvironment. Because the clinical consequences of genetic CatC deficiency in humans resulting in the elimination of NSPs are mild, small molecule inhibitors of CatC are assumed as safe drugs to reduce the NSP burden. Brensocatib, a nitrile CatC inhibitor is currently tested in a phase 3 clinical trial as a novel anti-inflammatory therapy for patients with bronchiectasis. However, recently developed CatC inhibitors possibly have protective effects beyond inflammation. In this review, we describe the pathophysiological function of CatC and discuss molecular mechanisms substantiating pharmacological CatC inhibition as a potential strategy for cancer treatment.

Copyright © 2021 Elsevier Inc. All rights reserved.

Keywords: Cancer; Inflammation; Inhibitor; Neutrophil; Protease; Treatment strategy

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