title: 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.
authors.affiliation: Molecular Therapeutics, School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL, UK.
authors.forename: Richard D A
authors.initials: RD
authors.lastname: Wilkinson
authors.affiliation: Molecular Therapeutics, School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL, UK.
authors.forename: Sinead M
authors.initials: SM
authors.lastname: Magorrian
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL, UK.
authors.forename: Rich
authors.initials: R
authors.lastname: Williams
authors.affiliation: Molecular Therapeutics, School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Young
authors.affiliation: Molecular Therapeutics, School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL, UK.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Small
authors.affiliation: Molecular Therapeutics, School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Scott
authors.affiliation: Molecular Therapeutics, School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL, UK.
authors.forename: Roberta E
authors.initials: RE
authors.lastname: Burden
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002403:Cathepsins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D018932:Chemokine CCL2; D000949:Histocompatibility Antigens Class II; C045084:invariant chain; D002403:Cathepsins; C028217:cathepsin S
keywords: cancer; chemokine; inflammation; microenvironment; protease