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

Journal of Leukocyte Biology

Ki-Up Lee²  Gil-Hong Park–⁵  Kyung-Mi Lee–⁵  In-Sun Park³  Pepper Schedin and⁴  In-Kyu Lee⁶  Young-Jun Shim¹  Bon-Hong Min¹  Byeong-Ho Kang¹  Hye-Sook Jeon¹ 

[1] Department of Pharmacology and –Biochemistry and BK Program in Biomedical Sciences, College of Medicine, Korea University, Seoul, Korea;Department of Internal Medicine, University of Ulsan, College of Medicine, Korea; Department of Anatomy, College of Medicine, Inha University, Korea;Department of Medicine, Division of Medical Oncology, University of Colorado-Denver, Colorado, USA –Biochemistry and BK Program in Biomedical Sciences, College of Medicine, Korea University, Seoul, Korea;–Biochemistry and BK Program in Biomedical Sciences, College of Medicine, Korea University, Seoul, Korea;Department of Internal Medicine and Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Korea;

关键词: MMP-9;    glycosylation;    ECM remodeling;    tumor invasion;    inflammation;   

DOI  :  10.1189/jlb.0311110

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

Unknown