title: Clusterin induces matrix metalloproteinase-9 expression via ERK1/2 and PI3K/Akt/NF-κB pathways in monocytes/macrophages.
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.
authors: Department of Pharmacology and Biochemistry, College of Medicine, Korea.
authors: Young-Jun
authors: YJ
authors: Shim
authors: Byeong-Ho
authors: BH
authors: Kang
authors: Hye-Sook
authors: HS
authors: Jeon
authors: In-Sun
authors: IS
authors: Park
authors: Ki-Up
authors: KU
authors: Lee
authors: In-Kyu
authors: IK
authors: Lee
authors: Gil-Hong
authors: GH
authors: Park
authors: Kyung-Mi
authors: KM
authors: Lee
authors: Pepper
authors: P
authors: Schedin
authors: Bon-Hong
authors: BH
authors: Min
mesh_terms: D000818:Animals; D002460:Cell Line; D051152:Clusterin / Q000378:metabolism* / Q000494:pharmacology; D004790:Enzyme Induction; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C495242:CLU protein, human; C495243:Clu protein, mouse; D051152:Clusterin; C498143:RELA protein, human; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse