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 journalArticlepeer-review

    62 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

    Keywords

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

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology
    • Cell Biology

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