Roles of Matrix Metalloproteinase-9 in Cancer Metastasis

Hyereen Kang,Sung-Wuk Jang 대한의생명과학회 2014 Biomedical Science Letters Vol.20 No.3

Matrix metalloproteinases (MMPs), also called matrixins, function in the extracellular environment of cells and degrade both matrix and non-matrix proteins. They are multidomain proteins and their activities are regulated by tissue inhibitor of metalloproteinases (TIMPs). The uncontrolled regulation of MMPs is involved in various pathologic processes, such as tumor invasion, migration, host immune escape, extravasation, angiogenesis, and tumor growth. Especially, matrix metalloproteinase-9 (MMP-9) is one of the metastasis-accelerating genes involved in metastasis of various types of human cancers. Here, we review the member of MMP family and discusses their domain structure and function, enzyme activation, the mechanism of inhibition by TIMPs. In particular, we focus the role of MMP-9 in relation to cancer metastasis.

Glaucine inhibits breast cancer cell migration and invasion by inhibiting MMP-9 gene expression through the suppression of NF-κB activation

Kang, Hyereen,Jang, Sung-Wuk,Pak, Jhang Ho,Shim, Sungbo Springer US 2015 MOLECULAR AND CELLULAR BIOCHEMISTRY - Vol.403 No.1

<P> Matrix metalloproteinase-9 (MMP-9) plays a central role in the invasion and metastasis of various types of cancer cells. Here, we demonstrate that glaucine, an alkaloid isolated from the plant<I> Corydalis turtschaninovii</I> tuber (Papaveraceae), can inhibit the migration and invasion of human breast cancer cells. We further show that glaucine significantly blocks phorbol 12-myristate 13-acetate (PMA)-induced MMP-9 expression and activity in a dose-dependent manner. Results from reporter gene and electrophoretic mobility shift assays revealed that glaucine inhibits MMP-9 expression by suppressing activation of the nuclear transcription factor nuclear factor-κB (NF-κB). Moreover, glaucine attenuates PMA-induced IκBα degradation and nuclear translocation of NF-κB. Finally, we also found that glaucine inhibits invasion and MMP-9 expression in the highly metastatic MDA-MB-231 breast cancer cell line. Taken together, our findings indicate that the MMP-9 inhibitory activity of glaucine and its abilities to attenuate IκBα and NF-κB activities may be therapeutically useful as a novel means of controlling breast cancer growth and invasiveness.</P>

<i>N</i>‐(4‐hydroxyphenyl)retinamide inhibits breast cancer cell invasion through suppressing NF‐KB activation and inhibiting matrix metalloproteinase‐9 expression

Kang, Hyereen,Lee, Minjae,Choi, Kyung‐,chul,Shin, Dong‐,Myoung,Ko, Jesang,Jang, Sung‐,Wuk Wiley Subscription Services, Inc., A Wiley Company 2012 Journal of cellular biochemistry Vol.113 No.9

<P><B>Abstract</B></P><P>Synthetic retinoid <I>N</I>‐(4‐hydroxyphenyl)retinamide (4‐HPR) has been reported to exhibit anti‐invasive and anti‐metastatic activities by suppressing the enzymatic activity of matrix metalloproteinase (MMP)‐9, but the underlying mechanism remains unclear. Here, we show that 4‐HPR blocks the activity of MMP‐9 in two ways: by reducing phorbol 12‐myristate 13‐acetate (PMA)‐induced MMP‐9 secretion and by suppressing cell invasion through the downregulation of MMP‐9 gene transcription in MCF‐7 breast cancer cells. 4‐HPR inhibits the transcriptional activity of MMP‐9 by reducing the DNA‐binding activity of NF‐κB on the MMP‐9 promoter as well as by inhibiting the degradation of IκBα, leading to cytoplasmic accumulation of NF‐κB. We also found that 4‐HPR inhibits invasion and MMP‐9 expression in the highly metastatic breast cancer cell line MDA‐MB‐231. Thus, 4‐HPR might be a potent anti‐invasive agent that works by suppressing MMP‐9 expression via the NF‐κB signaling pathway. J. Cell. Biochem. 113: 2845–2855, 2012. © 2012 Wiley Periodicals, Inc.</P>

A novel isoform of human LZIP negatively regulates the transactivation of the glucocorticoid receptor.

Kang, Hyereen,Kim, Yoon Suk,Ko, Jesang Endocrine Society 2009 Molecular endocrinology Vol.23 No.11

<P>The human leucine zipper protein (LZIP) is a basic leucine zipper transcription factor that is involved in leukocyte migration, tumor suppression, and endoplasmic reticulum stress-associated protein degradation. Although evidence suggests a diversity of roles for LZIP, its function is not fully understood, and the subcellular localization of LZIP is still controversial. We identified a novel isoform of LZIP and characterized its function in ligand-induced transactivation of the glucocorticoid receptor (GR) in COS-7 and HeLa cells. A novel isoform of human LZIP designated as 'sLZIP' contains a deleted putative transmembrane domain (amino acids 229-245) of LZIP and consists of 345 amino acids. LZIP and sLZIP were ubiquitously expressed in a variety of cell lines and tissues, with LZIP being much more common. sLZIP was mainly localized in the nucleus, whereas LZIP was located in the cytoplasm. Unlike LZIP, sLZIP was not involved in the chemokine-mediated signal pathway. sLZIP recruited histone deacetylases (HDACs) to the promoter region of the mouse mammary tumor virus luciferase reporter gene and enhanced the activities of HDACs, resulting in suppression of expression of the GR target genes. Our findings suggest that sLZIP functions as a negative regulator in glucocorticoid-induced transcriptional activation of GR by recruitment and activation of HDACs.</P>

Celastrol Inhibits Breast Cancer Cell Invasion via Suppression of NF-κB-mediated Matrix Metalloproteinase-9 Expression

Kim, Yoonseo,Kang, Hyereen,Jang, Sung-Wuk,Ko, Jesang S. Karger AG 2011 CELLULAR PHYSIOLOGY AND BIOCHEMISTRY Vol.28 No.2

<P>Background/Aims: Metastasis is one of the main causes of death for patients with malignant tumors. Induction of matrix metalloproteinase (MMP)-9 is particularly important for the invasiveness of various cancer cells. Celastrol, a triterpenoid isolated from the traditional Chinese medicine, is known to inhibit the proliferation of a variety of tumor cells, including leukemia, glioma, prostate and breast cancer cells. In this study, we investigated the effect of celastrol on the migration and invasion of human breast carcinoma cells. Results: We observed that celastrol suppressed phorbol 12-myristate 13-acetate (PMA)-induced invasion and migration of MCF-7 cells. We also found that celastrol inhibited PMA-induced MMP-9 expression at both the mRNA and the protein levels, and the proteolytic activity of MMP-9 in MCF-7 cells. Our results revealed that celastrol inhibited the transcriptional activity of MMP-9 by suppression of the DNA binding activity of NF-κB in the MMP-9 promoter, and inhibited degradation of IκBα and nuclear translocation of NF-κB. Conclusion: These results indicate that celastrol inhibits NF-κB-mediated MMP-9 expression, resulting in suppression of breast cancer cell invasion and migration that is induced by PMA. Celastrol is a potential agent for clinical use in preventing the invasion and metastasis of human malignant breast tumors.</P><P>Copyright © 2011 S. Karger AG, Basel</P>

Inhibitory effect of Trolox on the migration and invasion of human lung and cervical cancer cells.

Sung, Ho Joong,Kim, Yoonseo,Kang, Hyereen,Sull, Jae Woong,Kim, Yoon Suk,Jang, Sung-Wuk,Ko, Jesang D.A. Spandidos 2012 International journal of molecular medicine Vol.29 No.2

<P>The antioxidant 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) is implicated in migration and invasion of metastatic tumors. However, the molecular mechanism underlying the effect of Trolox on metastatic cancer cells is not known. We found that a non-cytotoxic dose of Trolox decreased phorbol 12-myristate 13-acetate (PMA)-induced invasion and migration of both A549 and HeLa cancer cells. We also found that Trolox suppressed both the expression and the proteolytic activity of matrix metalloproteinase-9 (MMP-9), and that the promoter activity of PMA-induced MMP-9 was inhibited by Trolox. Our results show that Trolox inhibits the transcriptional activity of MMP-9 by suppression of NF-κB transactivation. These results indicate that Trolox inhibits NF-κB-mediated MMP-9 expression, leading to the suppression of migration and invasion in lung and cervical cancer cells. Trolox is a potential agent for clinical use in preventing the invasion and metastasis of human malignant lung and cervical cancers.</P>