CCL2 is transcriptionally controlled by the lysosomal protease cathepsin S in a CD74-dependent manner

Abstract

Cathepsins S (CatS) has been implicated in numerous tumourigenic processes and here we document for the first time its involvement in CCL2 regulation within the tumour microenvironment. Analysis of syngeneic tumours highlighted reduced infiltrating macrophages in CatS depleted tumours. Interrogation of tumours and serum revealed genetic ablation of CatS leads to the depletion of several pro-inflammatory chemokines, most notably, CCL2. This observation was validated in vitro, where shRNA depletion of CatS resulted in reduced CCL2 expression. This regulation is transcriptionally mediated, as evident from RT-PCR analysis and CCL2 promoter studies. We revealed that CatS regulation of CCL2 is modulated through CD74 (also known as the invariant chain), a known substrate of CatS and a mediator of NFkB activity. Furthermore, CatS and CCL2 show a strong clinical correlation in brain, breast and colon tumours. In summary, these results highlight a novel mechanism by which CatS controls CCL2, which may present a useful pharmacodynamic marker for CatS inhibition.

Insulin-induced cytokine production in macrophages causes insulin resistance in hepatocytes

“…In light of the development of insulin resistance in the course of the metabolic syndrome, it is of note that inflammasome activation can result from overloading of macrophages with cholesterol or urate or from activation of the Toll-like receptor-4 by saturated fatty acids (18). Similarly to IL-1␤, the induction of the other cytokines and chemokines, IL-8, CCl2, IL-6, and possibly TNF␣, may be caused directly by an insulin-dependent activation of NF-B, since NF-B regulatory elements are found in the promoters of all of these cytokines (15,20,36). By contrast, the OSM promoter does not seem to contain an NF-B-binding site.…”

Tumor‐associated macrophages (TAMs) depend on ZEB1 for their cancer‐promoting roles

“…Data represent the mean with standard errors from at least four mice for each genotype. The EMBO Journal TAMs require ZEB1 for their tumor-promoting roles Marlies Cortés et al respectively; Aldh1a1 and Kit, two cancer stem cell markers whose expression is associated with tumor progression in ovarian and other cancers (Chau et al, 2011;Silva et al, 2011); Mdr1 (Abcb1), an efflux drug transporter associated with chemotherapy resistance (Gottesman et al, 2002); and Cd74, which is expressed by both F4/80 low macrophages and ovarian cancer cells and that activates CCL2 transcription and promotes tumor progression (Wilkinson et al, 2015;Gil-Yarom et al, 2017). Interestingly, Zeb1 was higher in ID8 cells isolated from wild-type mice than in those from Zeb1 (+/À) mice ( Fig 3E).…”

Proteases and cytokines as mediators of interactions between cancer and stromal cells in tumours

“…Within endosomes, cathepsin S is the key protease responsible for the cleavage of CD74 and liberation of its intracellular domain (CD74-ICD), being then translocated into the nucleus, where it interacts with NFκB, that in turn regulates the expression of CCL2/MCP-1, among others. Accordingly, downregulation of cathepsin S expression in cancer cells reduces macrophage recruitment to the tumour site and correlates with reduced tumour growth in mice ( Wilkinson et al, 2015). Hu et al (2014) demonstrated that activation of the uPA-uPAR axis in cancer cells increases gene expression and protein secretion of IL-4 via ERK1/2 signalling and TGF-β by a thus far unknown mechanism.…”