PuSH - Publication Server of Helmholtz Zentrum München

Korkmaz, B.* ; Lamort, A.-S. ; Domain, R.* ; Beauvillain, C.* ; Gieldon, A.* ; Yildirim, A.Ö. ; Stathopoulos, G.T. ; Rhimi, M.* ; Jenne, D. ; Kettritz, R.*

Cathepsin C inhibition as a potential treatment strategy in cancer.

Biochem. Pharmacol. 194, 114803 (2021)
Open Access Green as soon as Postprint is submitted to ZB.
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.
Additional Metrics?
Edit extra informations Login
Publication type Article: Journal article
Document type Review
Keywords Cancer ; Inflammation ; Inhibitor ; Neutrophil ; Protease ; Treatment Strategy; Dipeptidyl-peptidase-i; Neutrophil Extracellular Traps; Papillon-lefevre-syndrome; Crystal-structure; Serine Proteases; Active-site; Mouse Model; Granzyme-b; Dna Traps; Elastase
ISSN (print) / ISBN 0006-2952
e-ISSN 0006-2952
Quellenangaben Volume: 194, Issue: , Pages: 114803 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, England
Reviewing status Peer reviewed
Grants Deutsche Forschungsgemeinschaft (DFG)
German Centre for Lung Research (Deutsches Zentrum fur Lungenforschung, DZL)
target validation project for pharmaceutical development ALTERNATIVE of the German Ministry for Education and Research (Bundesministerium fur Bildung und Forschung, BMBF)
Graduate College (Graduiertenkolleg, GRK) of the German Research Society (Deutsche Forschungsgemeinschaft, DFG)
"Region Centre Val de Loire" (Project Pirana)
Ministere de l'Enseignement superieur et de la Recherche