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Article ; Online: A Simple Cell-Based Assay for the Detection of Surface Protein Shedding by Rhomboid Proteases.

Moncada-Pazos, Angela / Grieve, Adam Graham

Methods in molecular biology (Clifton, N.J.)

2018 Volume 1731, Page(s) 57–64

Abstract: Rhomboids are intramembrane serine proteases that cleave their substrates within or immediately adjacent to their transmembrane domains, a process known as regulated intramembrane proteolysis. In eukaryotes, two main types of rhomboid proteases can be ... ...

Abstract	Rhomboids are intramembrane serine proteases that cleave their substrates within or immediately adjacent to their transmembrane domains, a process known as regulated intramembrane proteolysis. In eukaryotes, two main types of rhomboid proteases can be distinguished based on their subcellular localization: mitochondrial rhomboids and secretase-type rhomboids that target the secretory pathway. The latter class can cleave and release the extracellular domain of all epidermal growth factor-like proteins in Drosophila and can liberate epidermal growth factor (EGF) in mammals, in a process known as ectodomain shedding. These released EGFs can then activate the EGF receptor (EGFR). EGFR signaling is crucial for mammalian development and is often deregulated in human cancer. Here we describe a cell-based protocol for detecting the ability of rhomboid proteases to release EGFR ligands into the medium. First, cells are transfected with the corresponding protease- and substrate-expressing vectors; second, cells condition the medium and accumulate shed protein. After this, protein lysates from cells and media are prepared and Western blotting is performed to detect the EGFR ligands that have been released into the medium.
MeSH term(s)	Animals ; COS Cells ; Cell Membrane/metabolism ; Cercopithecus aethiops ; Epidermal Growth Factor/metabolism ; ErbB Receptors/metabolism ; Ligands ; Membrane Proteins/metabolism ; Mitochondria/metabolism ; Protein Domains ; Serine Endopeptidases/metabolism ; Substrate Specificity
Chemical Substances	Ligands ; Membrane Proteins ; Epidermal Growth Factor (62229-50-9) ; ErbB Receptors (EC 2.7.10.1) ; Serine Endopeptidases (EC 3.4.21.-)
Language	English
Publishing date	2018-01-09
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-7595-2_6
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Article ; Online: The dual role of fibulins in tumorigenesis.

Obaya, Alvaro J / Rua, Susana / Moncada-Pazos, Angela / Cal, Santiago

Cancer letters

2012 Volume 325, Issue 2, Page(s) 132–138

Abstract: The human fibulin family consists of seven complex extracellular glycoproteins originally characterized as components of elastic fibers in connective tissue. However, beyond its structural role, fibulins are involved in complex biological processes such ... ...

Abstract	The human fibulin family consists of seven complex extracellular glycoproteins originally characterized as components of elastic fibers in connective tissue. However, beyond its structural role, fibulins are involved in complex biological processes such as cell adhesion, migration or proliferation. Indeed, they have proved to be essential elements in normal physiology, as shown by mouse models lacking these proteins, that evidence several developmental abnormalities and pathological features. Their relevance is also apparent in tumorigenesis, an aspect that has started to be intensely studied. Distinct fibulins are expressed in both tumor and stromal cells and are subjected to multiple expression regulations with either anti or pro-tumor effects. The mechanistic insights that underlie these observations are now commencing to emerge, portraying these proteins as very versatile and active constituents of connective tissue. The aim of this review is to highlight the most relevant connections between fibulins and cancer.
MeSH term(s)	ADAM Proteins/physiology ; ADAMTS1 Protein ; Animals ; Calcium-Binding Proteins/chemistry ; Calcium-Binding Proteins/deficiency ; Calcium-Binding Proteins/genetics ; Calcium-Binding Proteins/physiology ; Cell Transformation, Neoplastic ; Elastic Tissue/metabolism ; Elastic Tissue/ultrastructure ; Elastin/metabolism ; Extracellular Matrix/metabolism ; Extracellular Matrix Proteins/metabolism ; Gene Silencing ; Humans ; Mice ; Mice, Knockout ; Microfibrils/metabolism ; Microfibrils/ultrastructure ; Neoplasm Proteins/physiology ; Neoplasms/metabolism ; Neoplasms/ultrastructure ; Oligopeptides ; Protein Isoforms/chemistry ; Protein Isoforms/genetics ; Protein Isoforms/physiology
Chemical Substances	Calcium-Binding Proteins ; Extracellular Matrix Proteins ; Neoplasm Proteins ; Oligopeptides ; Protein Isoforms ; fibulin ; arginyl-glycyl-aspartic acid (78VO7F77PN) ; Elastin (9007-58-3) ; ADAM Proteins (EC 3.4.24.-) ; ADAMTS1 Protein (EC 3.4.24.-) ; ADAMTS1 protein, human (EC 3.4.24.-)
Language	English
Publishing date	2012-12-28
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2012.06.019
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Zs.A 1177: Show issues

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Article ; Online: Neurocan is a New Substrate for the ADAMTS12 Metalloprotease: Potential Implications in Neuropathies.

Fontanil, Tania / Mohamedi, Yamina / Moncada-Pazos, Angela / Cobo, Teresa / Vega, José A / Cobo, Juan Luis / García-Suárez, Olivia / Cobo, Juan / Obaya, Álvaro J / Cal, Santiago

Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology

2019 Volume 52, Issue 5, Page(s) 1003–1016

Abstract: Background/aims: The composition of the extracellular matrix (ECM) in the central nervous system (CNS) has several features that make it unique. For instance, it is remarkable for the presence of proteoglycans such as versican, brevican, and neurocan, ... ...

Abstract	Background/aims: The composition of the extracellular matrix (ECM) in the central nervous system (CNS) has several features that make it unique. For instance, it is remarkable for the presence of proteoglycans such as versican, brevican, and neurocan, some of which have been identified as substrates of different members of the ADAMTS family of secreted metalloproteases. Previous studies have associated ADAMTSs with the repair of the CNS, including recovery following degradation of glial scar tissue and the stimulation of axonal growth after brain injury. However, the involvement of ADAMTSs in diseases of the CNS is complex and not understood fully, and a current challenge is unraveling the precise roles of these metalloproteases in the brain. Methods: ADAMTS12 and neurocan gene expression was examined by quantitative PCR. Western blot analysis was employed to detect ADAMTS12 and neurocan protein expression in cell lines, and immunostaining techniques were used to detect neurocan in mouse brain tissues. Neurocan cleavage using recombinant ADAMTS1, ADAMTS4, ADAMTS5, and ADAMTS12 metalloproteases was evaluated by western blotting. Cell adhesion and migration were assessed using uncoated culture dishes or dishes coated with Matrigel or ECM components. Results: We identified neurocan as a novel component of brain ECM that can be cleaved by ADAMTS12. In addition, we showed that neurocan cleavage by ADAMTS12 altered the adhesive properties of the human neuroglioma H4 cell line. Moreover, immunohistochemical analysis of Adamts12-deficient mice revealed the significant accumulation of neurocan in the brain of neonatal mice. Conclusion: Overall, our results suggest that ADAMTS12 could be involved in the repair of the CNS through its ability to degrade neurocan. Moreover, it can be inferred that alterations in neurocan degradation processes could be associated with the pathogenesis of neurological disorders.
MeSH term(s)	ADAMTS Proteins/biosynthesis ; ADAMTS Proteins/genetics ; ADAMTS Proteins/metabolism ; Animals ; Cell Adhesion ; Cell Line, Tumor ; Cell Movement ; Chondroitin Sulfate Proteoglycans/genetics ; Chondroitin Sulfate Proteoglycans/metabolism ; Cranial Nerve Diseases/genetics ; Cranial Nerve Diseases/metabolism ; Cranial Nerve Diseases/pathology ; Gene Expression Regulation ; Humans ; Lectins, C-Type/genetics ; Lectins, C-Type/metabolism ; Mice ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Proteoglycans/genetics ; Proteoglycans/metabolism ; Proteolysis
Chemical Substances	Chondroitin Sulfate Proteoglycans ; Lectins, C-Type ; Ncan protein, mouse ; Nerve Tissue Proteins ; Proteoglycans ; NCAN protein, human (148684-98-4) ; ADAMTS Proteins (EC 3.4.24.-) ; ADAMTS12 protein, human (EC 3.4.24.-) ; Adamts12 protein, mouse (EC 3.4.24.-)
Language	English
Publishing date	2019-04-12
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1067572-3
ISSN	1421-9778 ; 1015-8987
ISSN (online)	1421-9778
ISSN	1015-8987
DOI	10.33594/000000069
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Zs.A 3160: Show issues

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Article ; Online: ADAMTS-12 metalloprotease is necessary for normal inflammatory response.

Moncada-Pazos, Angela / Obaya, Alvaro J / Llamazares, María / Heljasvaara, Ritva / Suárez, María F / Colado, Enrique / Noël, Agnès / Cal, Santiago / López-Otín, Carlos

The Journal of biological chemistry

2018 Volume 293, Issue 29, Page(s) 11648

Language	English
Publishing date	2018-09-12
Publishing country	United States
Document type	Journal Article ; Published Erratum
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.AAC118.004590
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Uc I Zs.108: Show issues

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Article ; Online: Effects of azacitidine on matrix metalloproteinase-9 in acute myeloid leukemia and myelodysplasia.

Bernal, Teresa / Moncada-Pazos, Angela / Soria-Valles, Clara / Gutiérrez-Fernández, Ana

Experimental hematology

2013 Volume 41, Issue 2, Page(s) 172–179

Abstract: Matrix metalloprotease-9 (MMP9) plays a critical role in acute myeloid leukemia (AML) by increasing the invasive properties of malignant myeloblasts. The role of this enzyme in high-risk myelodysplastic diseases (MDS) and the effect of azacitidine on its ...

Abstract	Matrix metalloprotease-9 (MMP9) plays a critical role in acute myeloid leukemia (AML) by increasing the invasive properties of malignant myeloblasts. The role of this enzyme in high-risk myelodysplastic diseases (MDS) and the effect of azacitidine on its expression in MDS and AML have not been studied in detail. In this work, we have analyzed the effect of different concentrations of azacitidine in two well-established, MDS-derived, acute myeloid leukemic cell lines: MOLM-13 and SKM-1. We have demonstrated that 1 μmol/L azacitidine decreases MMP9 DNA methylation levels and that this is correlated with a significant increase in messenger RNA expression in both cell lines. Surprisingly, changes in protein levels were minor. This paradoxic effect is explained by the drug-dependent induction of apoptosis that reduces the amount of active secreting cells. A balance between induced expression and apoptosis was established at an azacitidine concentration of 0.2 μmol/L in MOLM-13 cells. This dose significantly increased the invasive capacity of viable cells, as measured in the Matrigel assay. To evaluate the clinical relevance of this observation, we have examined the effect of azacitidine on MMP9 expression in bone marrow from five patients with MDS, with the finding that this drug significantly increased MMP9 protein levels in all analyzed patients after six cycles of treatment. Based on these results, we conclude that azacitidine increases MMP9 expression and may enhance invasiveness in vitro. Because all five patients relapsed, these findings might explain, at least partially, the clinical failure of the drug and the progression to a more aggressive disease.
MeSH term(s)	Aged ; Aged, 80 and over ; Anemia, Refractory, with Excess of Blasts/drug therapy ; Anemia, Refractory, with Excess of Blasts/enzymology ; Anemia, Refractory, with Excess of Blasts/pathology ; Antimetabolites/adverse effects ; Antimetabolites/therapeutic use ; Antimetabolites, Antineoplastic/pharmacology ; Apoptosis/drug effects ; Azacitidine/adverse effects ; Azacitidine/pharmacology ; Azacitidine/therapeutic use ; Catalysis/drug effects ; Cell Line, Tumor/drug effects ; Cell Line, Tumor/enzymology ; DNA Methylation/drug effects ; Disease Progression ; Drug Resistance, Neoplasm ; Enzyme Induction/drug effects ; Female ; Humans ; Leukemia, Monocytic, Acute/pathology ; Leukemia, Myelomonocytic, Acute/pathology ; Male ; Matrix Metalloproteinase 9/biosynthesis ; Matrix Metalloproteinase 9/genetics ; Middle Aged ; Neoplasm Invasiveness ; Neoplasm Proteins/biosynthesis ; Neoplasm Proteins/genetics ; Neoplasms, Second Primary/drug therapy ; Neoplasms, Second Primary/enzymology ; Neoplasms, Second Primary/pathology ; Promoter Regions, Genetic/drug effects ; Risk
Chemical Substances	Antimetabolites ; Antimetabolites, Antineoplastic ; Neoplasm Proteins ; Matrix Metalloproteinase 9 (EC 3.4.24.35) ; Azacitidine (M801H13NRU)
Language	English
Publishing date	2013-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	185107-x
ISSN	1873-2399 ; 0531-5573 ; 0301-472X
ISSN (online)	1873-2399
ISSN	0531-5573 ; 0301-472X
DOI	10.1016/j.exphem.2012.10.005
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Zs.A 922: Show issues

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Article ; Online: Neutrophil and Macrophage Cell Surface Colony-Stimulating Factor 1 Shed by ADAM17 Drives Mouse Macrophage Proliferation in Acute and Chronic Inflammation.

Tang, Jingjing / Frey, Jeremy M / Wilson, Carole L / Moncada-Pazos, Angela / Levet, Clémence / Freeman, Matthew / Rosenfeld, Michael E / Stanley, E Richard / Raines, Elaine W / Bornfeldt, Karin E

Molecular and cellular biology

2018 Volume 38, Issue 17

Abstract: Macrophages are prominent cells in acute and chronic inflammatory diseases. Recent studies highlight a role for macrophage proliferation post-monocyte recruitment under inflammatory conditions. Using an acute peritonitis model, we identify a significant ... ...

Abstract	Macrophages are prominent cells in acute and chronic inflammatory diseases. Recent studies highlight a role for macrophage proliferation post-monocyte recruitment under inflammatory conditions. Using an acute peritonitis model, we identify a significant defect in macrophage proliferation in mice lacking the leukocyte transmembrane protease ADAM17. The defect is associated with decreased levels of macrophage colony-stimulating factor 1 (CSF-1) in the peritoneum and is rescued by intraperitoneal injection of CSF-1. Cell surface CSF-1 (csCSF-1) is one of the substrates of ADAM17. We demonstrate that both infiltrated neutrophils and macrophages are major sources of csCSF-1. Furthermore, acute shedding of csCSF-1 following neutrophil extravasation is associated with elevated expression of iRhom2, a member of the rhomboid-like superfamily, which promotes ADAM17 maturation and trafficking to the neutrophil surface. Accordingly, deletion of hematopoietic iRhom2 is sufficient to prevent csCSF-1 release from neutrophils and macrophages and to prevent macrophage proliferation. In acute inflammation, csCSF-1 release and macrophage proliferation are self-limiting due to transient leukocyte recruitment and temporally restricted csCSF-1 expression. In chronic inflammation, such as atherosclerosis, the ADAM17-mediated lesional macrophage proliferative response is prolonged. Our results demonstrate a novel mechanism whereby ADAM17 promotes macrophage proliferation in states of acute and chronic inflammation.
MeSH term(s)	ADAM17 Protein/deficiency ; ADAM17 Protein/genetics ; ADAM17 Protein/metabolism ; Acute Disease ; Animals ; Carrier Proteins/antagonists & inhibitors ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Membrane/metabolism ; Cell Proliferation ; Chronic Disease ; Inflammation/metabolism ; Inflammation/pathology ; Macrophage Colony-Stimulating Factor/metabolism ; Macrophages/metabolism ; Macrophages/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Models, Biological ; Neutrophils/metabolism ; Neutrophils/pathology ; Peritonitis/metabolism ; Peritonitis/pathology ; Receptors, LDL/deficiency ; Receptors, LDL/genetics ; Solubility
Chemical Substances	Carrier Proteins ; Receptors, LDL ; iRhom2 protein, mouse ; Macrophage Colony-Stimulating Factor (81627-83-0) ; ADAM17 Protein (EC 3.4.24.86) ; Adam17 protein, mouse (EC 3.4.24.86)
Language	English
Publishing date	2018-08-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00103-18
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Zs.A 1666: Show issues

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Article: Expanding the complexity of the human degradome: polyserases and their tandem serine protease domains.

Cal, Santiago / Moncada-Pazos, Angela / Lopez-Otin, Carlos

Frontiers in bioscience : a journal and virtual library

2007 Volume 12, Page(s) 4661–4669

Abstract: The large and growing number of protease genes identified in the human genome, more than 560, reflects the complexity and relevance of these enzymes in multiple biological processes. As part of our studies on the human degradome--which is defined as the ... ...

Abstract	The large and growing number of protease genes identified in the human genome, more than 560, reflects the complexity and relevance of these enzymes in multiple biological processes. As part of our studies on the human degradome--which is defined as the complete set of human protease genes--we have recently identified and cloned three complex polyserine proteases called polyserases. Polyserase-1 is a member of the type-II transmembrane serine protease (TTSP) family of proteolytic enzymes that undergoes a series of post-translational processing events to generate three distinct and independent serine protease domains called serase-1, -2, and -3. Polyserase-2 is a secreted enzyme that also possesses three serine protease domains, but they remain as an integral part of the initial protein product. Finally, polyserase-3 is also a secreted enzyme that contains two serine protease domains embedded in the same polypeptide chain. Despite all three human polyserases share this complex molecular design characterized by the presence of several catalytic domains in their structure, they also exhibit distinctive features including unique expression patterns and different enzymatic properties. At present, the putative functional advantages derived from the complex structural organization of polyserases remain unknown, but the widespread occurrence of these enzymes in mammalian degradomes provides additional evidence about the complexity of proteolytic systems in these organisms.
MeSH term(s)	Animals ; Humans ; Membrane Proteins/chemistry ; Membrane Proteins/metabolism ; Serine Endopeptidases/chemistry ; Serine Endopeptidases/metabolism
Chemical Substances	Membrane Proteins ; Serine Endopeptidases (EC 3.4.21.-)
Language	English
Publishing date	2007-05-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2141320-4
ISSN	1093-9946
ISSN	1093-9946
DOI	10.2741/2415
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Zs.A 5867: Show issues

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Article ; Online: Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16.

Maruthappu, Thiviyani / Chikh, Anissa / Fell, Benjamin / Delaney, Paul J / Brooke, Matthew A / Levet, Clemence / Moncada-Pazos, Angela / Ishida-Yamamoto, Akemi / Blaydon, Diana / Waseem, Ahmad / Leigh, Irene M / Freeman, Matthew / Kelsell, David P

Nature communications

2017 Volume 8, Page(s) 14174

Abstract: Keratin 16 (K16) is a cytoskeletal scaffolding protein highly expressed at pressure-bearing sites of the mammalian footpad. It can be induced in hyperproliferative states such as wound healing, inflammation and cancer. Here we show that the inactive ... ...

Abstract	Keratin 16 (K16) is a cytoskeletal scaffolding protein highly expressed at pressure-bearing sites of the mammalian footpad. It can be induced in hyperproliferative states such as wound healing, inflammation and cancer. Here we show that the inactive rhomboid protease RHBDF2 (iRHOM2) regulates thickening of the footpad epidermis through its interaction with K16. K16 expression is absent in the thinned footpads of irhom2
MeSH term(s)	Animals ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Line ; Cell Proliferation/physiology ; Cytoskeleton/physiology ; Down-Regulation ; Epidermal Cells ; Epidermis/physiology ; Esophageal Neoplasms/genetics ; Esophageal Neoplasms/pathology ; Female ; Fibroblasts ; Gain of Function Mutation ; Humans ; Intracellular Signaling Peptides and Proteins ; Keratin-16/metabolism ; Keratin-6/metabolism ; Keratinocytes/physiology ; Keratoderma, Palmoplantar/genetics ; Keratoderma, Palmoplantar/pathology ; Male ; Mice ; Mice, Knockout ; Pressure ; RNA, Small Interfering/metabolism ; Stress, Physiological/physiology ; Tissue Culture Techniques ; Up-Regulation ; Wound Healing/physiology
Chemical Substances	Carrier Proteins ; Intracellular Signaling Peptides and Proteins ; KRT16 protein, human ; KRT6A protein, human ; Keratin-16 ; Keratin-6 ; Krt16 protein, mouse ; RHBDF2 protein, human ; RNA, Small Interfering ; iRhom2 protein, mouse
Language	English
Publishing date	2017-01-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/ncomms14174
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Article ; Online: Cleavage of Fibulin-2 by the aggrecanases ADAMTS-4 and ADAMTS-5 contributes to the tumorigenic potential of breast cancer cells.

Fontanil, Tania / Álvarez-Teijeiro, Saúl / Villaronga, M Ángeles / Mohamedi, Yamina / Solares, Laura / Moncada-Pazos, Angela / Vega, José A / García-Suárez, Olivia / Pérez-Basterrechea, Marcos / García-Pedrero, Juana M / Obaya, Alvaro J / Cal, Santiago

Oncotarget

2017 Volume 8, Issue 8, Page(s) 13716–13729

Abstract: Fibulin-2 participates in the assembly of extracellular matrix components through interactions with multiple ligands and promotes contacts between cells and their surrounding environment. Consequently, identification of processes that could lead to an ... ...

Abstract	Fibulin-2 participates in the assembly of extracellular matrix components through interactions with multiple ligands and promotes contacts between cells and their surrounding environment. Consequently, identification of processes that could lead to an altered Fibulin-2 could have a major impact not only in the maintenance of tissue architecture and morphogenesis but also in pathological situations including cancer. Herein, we have investigated the ability of the secreted metalloproteases ADAMTS-4 and ADAMTS-5 to digest Fibulin-2. Using in vitro approaches and cultured breast cancer cell lines we demonstrate that Fibulin-2 is a better substrate for ADAMTS-5 than it is for ADAMTS-4. Moreover, Fibulin-2 degradation is associated to an enhancement of the invasive potential of T47D, MCF-7 and SK-BR-3 cells. We have also found that conditioned medium from MCF-7 cells that simultaneously overexpress Fibulin-2 and ADAMTS-5 significantly induced the migratory and invasive ability of normal breast fibroblasts using 3D collagen matrices. Immunohistochemical analysis highlights the close proximity or partial overlap of both Fibulin-2 and ADAMTS-5 in breast tumor samples. Additionally, proteolytic products derived from a potential degradation of Fibulin-2 by ADAMTS-5 were also identified in these samples. Finally, we also show that the cleavage of Fibulin-2 by ADAMTS-5 is counteracted by ADAMTS-12, a metalloprotease that interacts with Fibulin-2. Overall, our results provide direct evidence indicating that Fibulin-2 is a novel substrate of ADAMTS-5 and that this proteolysis could alter the cellular microenvironment affecting the balance between protumor and antitumor effects associated to both Fibulin-2 and the ADAMTSs metalloproteases.
MeSH term(s)	ADAMTS4 Protein/metabolism ; ADAMTS5 Protein/metabolism ; Breast Neoplasms/enzymology ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Calcium-Binding Proteins/metabolism ; Carcinogenesis ; Cell Line, Tumor ; Extracellular Matrix Proteins/metabolism ; Female ; Fibroblasts/pathology ; Humans ; MCF-7 Cells ; Spheroids, Cellular ; Transfection ; Tumor Microenvironment
Chemical Substances	Calcium-Binding Proteins ; Extracellular Matrix Proteins ; fibulin 2 ; ADAMTS5 Protein (EC 3.4.24.-) ; ADAMTS5 protein, human (EC 3.4.24.-) ; ADAMTS4 Protein (EC 3.4.24.82) ; ADAMTS4 protein, human (EC 3.4.24.82)
Language	English
Publishing date	2017-02-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.14627
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Article ; Online: The nutraceutical flavonoid luteolin inhibits ADAMTS-4 and ADAMTS-5 aggrecanase activities.

Moncada-Pazos, Angela / Obaya, Alvaro J / Viloria, Cristina G / López-Otín, Carlos / Cal, Santiago

Journal of molecular medicine (Berlin, Germany)

2011 Volume 89, Issue 6, Page(s) 611–619

Abstract: A disintegrin and metalloprotease with thrombospondin domains (ADAMTS)-4 (aggrecanase-1) and ADAMTS-5 (aggrecanase-2) are metalloproteases involved in articular cartilage degradation and represent potential therapeutic targets in arthritis treatment. We ... ...

Abstract	A disintegrin and metalloprotease with thrombospondin domains (ADAMTS)-4 (aggrecanase-1) and ADAMTS-5 (aggrecanase-2) are metalloproteases involved in articular cartilage degradation and represent potential therapeutic targets in arthritis treatment. We explore herein the ability of different natural compounds to specifically block the destructive action of these enzymes. Following a preliminary screening using carboxymethylated transferrin as substrate, we focused our interest on luteolin due to its inhibitory effect on ADAMTS-4 and ADAMTS-5 activities using aggrecan and fluorogenic peptides as substrates. However, matrix metalloproteinases (MMPs) activities on these substrates result less affected by this flavonoid. Moreover, incubation of mouse chondrogenic ATDC5 cells in the presence of luteolin clearly decreases the release of aggrecan fragments mediated by aggrecanases under the same conditions in which aggrecanolysis mediated by MMPs is detected. Additionally, glycosaminoglycan levels in culture medium of murine cartilage explants stimulated with interleukin-1-alpha plus retinoic acid are reduced by the presence of the flavonoid. This inhibition takes place through blockade of ADAMTS-mediated aggrecanolysis, while MMPs activity is not or poorly affected. These results suggest that luteolin could be employed as a prototypic modifying disease-agent to create new chondroprotective compounds aimed to specifically block the unwanted aggrecanase activities in arthritic diseases.
MeSH term(s)	ADAM Proteins/antagonists & inhibitors ; ADAMTS4 Protein ; ADAMTS5 Protein ; Aggrecans/metabolism ; Animals ; Arthritis/pathology ; Cartilage, Articular/metabolism ; Cartilage, Articular/pathology ; Cells, Cultured ; Chondrocytes/drug effects ; Chondrocytes/metabolism ; Endopeptidases/metabolism ; Extracellular Matrix Proteins/metabolism ; Glycosaminoglycans/analysis ; Interleukin-1alpha/pharmacology ; Luteolin/metabolism ; Luteolin/pharmacology ; Matrix Metalloproteinases/metabolism ; Metalloproteases/chemistry ; Metalloproteases/metabolism ; Mice ; Procollagen N-Endopeptidase/antagonists & inhibitors ; Tretinoin/pharmacology
Chemical Substances	Aggrecans ; Extracellular Matrix Proteins ; Glycosaminoglycans ; Interleukin-1alpha ; Tretinoin (5688UTC01R) ; Endopeptidases (EC 3.4.-) ; Metalloproteases (EC 3.4.-) ; ADAM Proteins (EC 3.4.24.-) ; ADAMTS5 Protein (EC 3.4.24.-) ; ADAMTS5 protein, human (EC 3.4.24.-) ; Matrix Metalloproteinases (EC 3.4.24.-) ; Procollagen N-Endopeptidase (EC 3.4.24.14) ; ADAMTS4 Protein (EC 3.4.24.82) ; ADAMTS4 protein, human (EC 3.4.24.82) ; Adamts4 protein, mouse (EC 3.4.24.82) ; aggrecanase (EC 3.4.99.-) ; Luteolin (KUX1ZNC9J2)
Language	English
Publishing date	2011-03-02
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1223802-8
ISSN	1432-1440 ; 0946-2716
ISSN (online)	1432-1440
ISSN	0946-2716
DOI	10.1007/s00109-011-0741-7
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