Authors:
Sally Thirkettle, Julie Decock, Hugh Arnold, Caroline J. Pennington, Diane M. Jaworski, and Dylan R. Edwards
Summary:
Matrix metalloproteinase-8 (MMP-8) is a tumor suppressive protease that cleaves numerous substrates including matrix proteins and chemokines. In particular MMP-8 proteolytically activates interleukin-8 (IL-8) and thereby regulates neutrophil chemotaxis in vivo. We have explored the effects of expression of either a wild-type (wt) or catalytically inactive (E198A) mutant version of MMP-8 in human breast cancer cell lines. Analysis of serum-free conditioned media from three breast cancer cell lines (MCF-7, SK-BR-3 and MDA-MB-231) expressing wt MMP-8 revealed elevated levels of interleukin-6 (IL-6) and IL-8. This increase was mirrored at the mRNA level, and was dependent on MMP-8 catalytic activity. However, sustained expression of wt MMP-8 by breast cancer cells was non-permissive for long-term growth, as shown by reduced colony formation compared to cells expressing either control vector or E198A mutant MMP-8. In long term culture of transfected MDA-MB-231 cells expression of wt but not E198A mutant MMP8 was lost, with IL-6 and IL-8 levels returning to baseline. Rare clonal isolates of MDA-MB-231 cells expressing wt MMP-8 were generated and these showed constitutively high levels of IL-6 and IL-8, though production of the interleukins was no longer dependent upon MMP-8 activity. These studies support a causal connection between MMP-8 activity and the IL-6/IL-8 network, with an acute response to MMP-8 involving induction of the pro-inflammatory mediators, which may in part serve to compensate for the deleterious effects of MMP-8 on breast cancer cell growth. This axis may be relevant to the recognised ability of MMP-8 to orchestrate the innate immune system in inflammation in vivo.
Source:
The Journal of Biological Chemistry; (04/30/13)