Matrix metalloproteinase and G protein coupled receptors: Co-conspirators in the pathogenesis of autoimmune disease and cancer
Section snippets
Matrix Metalloproteinase-1 (MMP-1), rheumatoid arthritis (RA), and cancer
MMPs are a family of zinc-dependent endopeptidases that function at neutral pH and that are responsible for the degradation of the extracellular matrix [2], [3], [4]. While low levels of these enzymes are essential for normal homeostasis, high levels are implicated in the pathology of several diseases. Although many MMPs are elevated in these conditions, MMP-1 has a particularly prominent role. Collagen (types I, II and III) is the body's most abundant protein, comprising 30% of all protein,
Regulation of MMP-1 gene expression
MMP expression is tightly regulated and occurs primarily at the level of transcription [2], [3], [4], [7]. In normal tissues, basal/constitutive expression is low, but is induced in response to growth factors and cytokines that activate signal transduction pathways (Fig. 1). The molecular mechanisms of transcriptional activation of several MMPs, including MMP-1, at the promoter are well characterized and comprise the Activator Protein-1 (AP-1) element in the proximal region of the promoter at
Carcinoma associated fibroblasts (CAFs), MMP-1 and CXCR4
While cancer research has traditionally focused on the tumor cells, host/tumor cell interactions in the tumor microenvironment are increasingly recognized as critical components of tumor development and progression [10], [11]. These interactions between the tumor and adjacent stromal cells result in the production of stromal factors, such as growth factors, chemokines, cytokines, proteases, and vascular-stimulating factors [12], [13], all of which can contribute to the growth of the primary
Endothelial cells, Protease Activated Receptor-1 (PAR-1) and MMP-1
The function of another G protein-coupled receptor, PAR-1, is directly linked to the enzymatic activity of MMP-1. Among all the MMPs, MMP-1 has the unique ability to cleave PAR-1 [34], with subsequent activation of signal transduction pathways and alterations in the expression of downstream genes. This unique ability to cleave PAR-1 gives MMP-1 a powerful role in controlling cell behavior.
As an example, we found that by silencing MMP-1 expression in a human melanoma cell line with shRNA
Therapeutic strategies that target MMP-1 and G protein-coupled receptors
RA and cancer share several therapeutic strategies, including the use of chemotherapeutic agents such as methotrexate, antibodies directed at cytokines/growth factors and their receptors, and/or small molecule inhibitors of signal transduction pathways ([3], [4], [49], [50], [51]; www.Cancer.org). In cancers, these treatments are often successful, but they may also eventually fail, resulting in relapse as tumors mutate and become resistant. Since stromal cells are recognized as critical
Concluding comments
As predicted by Sporn and Harris three decades ago, our knowledge of the precise molecular mechanisms that are driving non-malignant proliferative diseases (such as RA) and malignancies (such as breast cancer and melanoma) has grown enormously. This new information has re-enforced the original concept that these two seemingly disparate categories of diseases share many common properties, and the analogy between the reactive stroma in the tumor microenvironment and the pannus of RA has become
Acknowledgement
Supported by grants NIH-AR-25699 and NIH-CA-77267 to C.E.B., and by T32-CA-009658 to S.M.E., T32-AI-07363 to J.S.B., and T32-AR-07576 to A.C.S. and P.S.B.
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2022, BiochimieCitation Excerpt :Based on sequence and function, GPCRs are categorized into six classes, namely Class A-rhodopsin-like receptors, Class B-secretin family, Class C-metabotropic glutamate receptors, Class D-fungal mating pheromone receptors, Class E-cAMP receptors, and Class F-frizzled (FZD) and smoothened (SMO) receptors [15], where Class A-GPCRs are the most immensely investigated GPCR drug target. GPCRs have been implicated in the pathogenesis of several diseases including the cardiovascular disease [16], Alzheimer's disease [17], endocrine disorders [18], inflammatory bowel disease [19,20], autoimmune disease and cancer [21]. It is estimated that as much as 40% of the approved clinical drugs exert their action by targeting GPCRs [22,23].
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2020, Toxicology in VitroCitation Excerpt :Growing evidence has also demonstrated that MMPs can exhibit the pleotropic function in cell proliferation, apoptosis, host defense, and carcinogenesis by enzymatically degrading components of the extracellular matrix (Xie et al., 2017; Mannello et al., 2005) and that intracnuclear MMPs promote DNA damage, followed by apoptosis (Hill et al., 2012; Kimura-Ohba and Yang, 2016). Similarly, MMPs and G protein coupled receptors function as coworkers in autoimmune disease- and cancer-related lesion development (Eck et al., 2009), and small nucleolar RNA, C/D box genes can contribute to carcinogenesis by involving some RNA methylation, including ribosomal RNAs, transfer RNAs, and small nuclear RNAs. Reverse immune response between autoimmune disease and cancer (immune suppression) is induced, and both the volume and potential of mitochondria increase in cancer stem cells.
Proteases and their inhibitors as prognostic factors for high-grade serous ovarian cancer
2019, Pathology Research and PracticeCitation Excerpt :Over the years, high-grade serous ovarian cancer (HGSOC), a specific molecular subtype of ovarian cancer, has emerged as the most significant disease in terms of incidence and in terms of poor prognosis [6,7]. It has been repeatedly shown that different members of the degradome, comprising proteases, protease non-proteolytic homologues and inhibitors, have been involved in progression, invasion and metastasis of many cancer types, including ovarian cancer [8–14]. We have previously demonstrated that: (a) Matrix Metalloproteinase 2 (MMP-2) expression by ovarian cancer peritoneal cells was associated with a decreased specific survival [15]; (b) MMP-1 overexpression tended to be associated with a higher risk of progression [16,17]; (c) Tissue Inhibitor of Metalloproteinase-3 (TIMP-3) expression was downregulated in chemoresistant ovarian cancer [18]; (d) MMP-14 expression was associated with a lower risk of complete response to treatment [19], yet MMPs are now recognized as more often than not being beneficial for survival by providing essential host defense functions by cleaving bioactive mediators [20–22].
Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders
2017, Progress in Molecular Biology and Translational ScienceSynthesis of chiral ND-322, ND-364 and ND-364 derivatives as selective inhibitors of human gelatinase
2015, Bioorganic and Medicinal ChemistryCitation Excerpt :Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that regulate functions of the extracellular matrix (ECM),1 which are implicated in cancer growth,2–4 tumor metastasis and angiogenesis,5–7 arthritis,8,9 connective tissue diseases,10,11 inflammation,12 cardiovascular,13,14 neurological,15,16 and autoimmune diseases.17,18