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

53 Citations (Scopus)

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
Pages (from-to)761-769
Number of pages9
JournalJournal of Leukocyte Biology
Volume90
Issue number4
DOIs
Publication statusPublished - 2011 Oct 1

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Immunology

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