ausblenden:
Schlagwörter:
-
Zusammenfassung:
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.
