Clusterin induces matrix metalloproteinase-9 expression via ERK1/2 and PI3K/Akt/NF-κB pathways in monocytes/macrophages

Young Jun Shim, Byeong Ho Kang, Hye Sook Jeon, In Sun Park, Ki Up Lee, In Kyu Lee, Gil Hong Park, Kyung Mi Lee, Pepper Schedin, Bon Hong Min

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

Most solid tumor tissues possess a significant population of macrophages, which are known to be closely linked with tumor progression and metastasis. Clusterin has been reported to be overexpressed in various tumors and to have a tumor-promoting role. As clusterin induction and macrophage infiltration occur concurrently at the tumor site, it raises a possibility that clusterin may regulate the function of macrophages via facilitating ECM remodeling. Here, we demonstrate for the first time the expression of MMP-9 by clusterin in human primary monocytes as well as human and murine macrophage cell lines, THP-1, and Raw264.7. MMP-9 expression was accompanied by increased enzymatic activity, as revealed by gelatin zymography. The MMP-9 activity promoted by clusterin was found to be dependent on the activation of ERK1/2 and PI3K/Akt but not p38 or JNK pathways. Inhibition of PI3K activity did not affect the activation of ERK1/2 and vice versa, indicating that the two pathways were independently operated to stimulate MMP-9 activity. Moreover, clusterin facilitated nuclear translocation of NF-κB p65 along with IκB-α degradation and phosphorylation, which was critical for MMP-9 expression. As NF-κB is a central regulator of inflammation, clusterin may provide a molecular link between inflammation and cancer via up-regulating NF-κB and MMP-9. Collectively, these data highlight a novel role of clusterin as a stimulator for MMP-9 expression in macrophages, which may contribute to the tissue reorganization by serving as a modulator for ECM degradation.

Original languageEnglish (US)
Pages (from-to)761-769
Number of pages9
JournalJournal of Leukocyte Biology
Volume90
Issue number4
DOIs
StatePublished - Oct 1 2011

Keywords

  • ECM remodeling
  • Glycosylation
  • Inflammation
  • MMP-9
  • Tumor invasion

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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    Shim, Y. J., Kang, B. H., Jeon, H. S., Park, I. S., Lee, K. U., Lee, I. K., Park, G. H., Lee, K. M., Schedin, P., & Min, B. H. (2011). Clusterin induces matrix metalloproteinase-9 expression via ERK1/2 and PI3K/Akt/NF-κB pathways in monocytes/macrophages. Journal of Leukocyte Biology, 90(4), 761-769. https://doi.org/10.1189/jlb.0311110