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

Richard D.A. Wilkinson; Sinead M. Magorrian; Rich Williams; Andrew Young; Donna M. Small; Christopher J. Scott; Roberta E. Burden

doi:10.18632/oncotarget.5065

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Research Papers:

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

Richard D.A. Wilkinson _, Sinead M. Magorrian, Rich Williams, Andrew Young, Donna M. Small, Christopher J. Scott and Roberta E. Burden

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Oncotarget. 2015; 6:29725-29739. https://doi.org/10.18632/oncotarget.5065

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Abstract

Richard D.A. Wilkinson1,*, Sinead M. Magorrian1*, Rich Williams2, Andrew Young1, Donna M. Small1, Christopher J. Scott1, Roberta E. Burden1,*

1Molecular Therapeutics, School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL

2Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL

*These authors have contributed equally to this work

Correspondence to:

Roberta E. Burden, e-mail: [email protected]

Keywords: protease, microenvironment, inflammation, chemokine, cancer

Received: May 11, 2015 Accepted: August 14, 2015 Published: August 22, 2015

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.

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Research Papers:

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

Abstract