Matrix Metalloproteinases

Vargová, Viola; Pytliak, Marek; Mechírová, Viola

doi:10.1007/978-3-0348-0364-9_1

Cited by 58 publications

(66 citation statements)

References 125 publications

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“…It is well known that MMP2 and MMP9 are involved in the systemic dissemination of tumors 30. Furthermore, high levels of MMP2 and MMP9 have been found in pancreatic cancer tissue 31.…”

Section: Resultsmentioning

confidence: 99%

A blockade of PD-L1 produced antitumor and antimetastatic effects in an orthotopic mouse pancreatic cancer model via the PI3K/AkT/MTOR signaling pathway

Zhao

Li²,

Liu³

et al. 2017

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BackgroundPancreatic cancer is one of the most aggressive and intractable malignant tumors, and most deaths from pancreatic cancer are related to metastases. It has been demonstrated in vitro that overexpression of programmed death-ligand 1 (PD-L1) correlates with a lack of phosphatase and tensin homologue (PTEN) expression in pancreatic cancer tissue. This loss of PTEN expression may aberrantly activate the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, and thereby promote tumor cell survival, proliferation, and disease progression. In this study, we investigated the potential therapeutic effect of blockading PD-L1 expression on the progression of pancreatic cancer and its spontaneous liver metastases in vivo by inhibiting the PI3K/Akt/mTOR signaling pathway.MethodsWe investigated the effect of blockading PD-L1 in an orthotopic pancreatic cancer mouse model. The pancreatic tumor weights and inhibition ratios were determined after treatment with antimouse PD-L1 antibody for 5 weeks. We used immunohistochemistry methods to investigate PD-L1 expression in pancreatic cancer tissue and spontaneous liver metastasis tissue. The levels of mRNA and protein expression for various components involved in the PI3K/Akt/mTOR signaling pathway as well as for matrix metalloproteinases-2 and -9 (MMP2 and MMP9) were measured by reverse transcription polymerase chain reaction (RT-PCR) and Western blot methods, respectively.ResultsBlockading PD-L1 significantly inhibited tumor growth and decreased the levels of PD-L1 expression in tumor tissue. Furthermore, the levels of PTEN mRNA and protein expression were elevated, while the levels of phospho-Akt (p-Akt) and phospho-mTOR (p-mTOR) protein were decreased in pancreatic cancer and liver metastasis tissues after establishing a PD-L1 blockade. In addition, a PD-L1 blockade decreased the levels of MMP2 and MMP9 mRNA and protein expression in tumor tissues.ConclusionOur results suggest that a blockade of PD-L1 may inhibit the growth and metastasis of pancreatic cancer by modulating the PI3K/Akt/mTOR pathway.

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“…It is well known that MMP2 and MMP9 are involved in the systemic dissemination of tumors 30. Furthermore, high levels of MMP2 and MMP9 have been found in pancreatic cancer tissue 31.…”

Section: Resultsmentioning

confidence: 99%

A blockade of PD-L1 produced antitumor and antimetastatic effects in an orthotopic mouse pancreatic cancer model via the PI3K/AkT/MTOR signaling pathway

Zhao

Li²,

Liu³

et al. 2017

OTT

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“…An inherent characteristic of the triple helix of fibrillar collagen is its resistance to proteolysis by most endogenous peptidases. Human enzymes that can cleave this structure include several collagenases from the family of matrix metallopeptidases (MMP-1, -8, -13 and -14) (Vargova et al , 2012 ), the serine peptidase neutrophil elastase (Kafienah et al , 1998b ) and cysteine cathepsin K. While MMPs and neutrophil elastase cleave the triple helix at a single position within an unwound region (Kafienah et al , 1998b ;Chung et al , 2004 ), cathepsin K can cleave at multiple positions along the molecule, as illustrated in Figure 1 . Multiple cathepsin K cleavage sites have been identified in collagen molecules from different animal sources (Figure 1).…”

Section: Collagenolytic Activity Of Cathepsin K At the Molecular Levelmentioning

confidence: 98%

Cathepsin K: a unique collagenolytic cysteine peptidase

Novinec

Lenarčič²

2013

Biological Chemistry

121

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Cathepsin K has emerged as a promising target for the treatment of osteoporosis in recent years. Initially identified as a papain-like cysteine peptidase expressed in high levels in osteoclasts, the important role of this enzyme in bone metabolism was highlighted by the finding that mutations in the CTSK gene cause the rare recessive disorder pycnodysostosis, which is characterized by severe bone anomalies. At the molecular level, the physiological role of cathepsin K is reflected by its unique cleavage pattern of type I collagen molecules, which is fundamentally different from that of other endogenous collagenases. Several cathepsin K inhibitors have been developed to reduce the excessive bone matrix degradation associated with osteoporosis, with the frontrunner odanacatib about to successfully conclude Phase 3 clinical trials. Apart from osteoclasts, cathepsin K is expressed in different cell types throughout the body and is involved in processes of adipogenesis, thyroxine liberation and peptide hormone regulation. Elevated activity of cathepsin K has been associated with arthritis, atherosclerosis, obesity, schizophrenia, and tumor metastasis. Accordingly, its activity is tightly regulated via multiple mechanisms, including competitive inhibition by endogenous macromolecular inhibitors and allosteric regulation by glycosaminoglycans. This review provides a state-of-the-art description of the activity of cathepsin K at the molecular level, its biological functions and the mechanisms involved in its regulation.

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“…Cathepsin K is a highly potent peptidase that can cleave most extracellular proteins, including the triple helix of type I and type II collagens. In contrast to other endogenous collagenases, such as neutrophil elastase and matrix metallopeptidase-1, -8, -13, -14, and -18, which cleave the collagen triple helix at a single position (103,104) , cathepsin K can cleave at multiple positions along the molecule (105,106) . Excessive activity of cathepsin K has been associated with osteoporosis and several cathepsin K inhibitors are currently under investigation as potential therapeutics (107) , as will be discussed in more detail later.…”

Section: Cathepsin L-like Peptidasesmentioning

confidence: 99%

Papain-like peptidases: structure, function, and evolution

Novinec

Lenarčič²

2013

BioMolecular Concepts

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Papain-like cysteine peptidases are a diverse family of peptidases found in most known organisms. In eukaryotes, they are divided into multiple evolutionary groups, which can be clearly distinguished on the basis of the structural characteristics of the proenzymes. Most of them are endopeptidases; some, however, evolved into exopeptidases by obtaining additional structural elements that restrict the binding of substrate into the active site. In humans, papain-like peptidases, also called cysteine cathepsins, act both as non-specific hydrolases and as specific processing enzymes. They are involved in numerous physiological processes, such as antigen presentation, extracellular matrix remodeling, and hormone processing. Their activity is tightly regulated and dysregulation of one or more cysteine cathepsins can result in severe pathological conditions, such as cardiovascular diseases and cancer. Other organisms can utilize papainlike peptidases for different purposes and they are often part of host-pathogen interactions. Numerous parasites, such as Plasmodium and flukes, utilize papain-like peptidases for host invasion, whereas plants, in contrast, use these enzymes for host defense. This review presents a state-of-the-art description of the structure and phylogeny of papain-like peptidases as well as an overview of their physiological and pathological functions in humans and in other organisms.

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Matrix Metalloproteinases

Cited by 58 publications

References 125 publications

A blockade of PD-L1 produced antitumor and antimetastatic effects in an orthotopic mouse pancreatic cancer model via the PI3K/AkT/MTOR signaling pathway

A blockade of PD-L1 produced antitumor and antimetastatic effects in an orthotopic mouse pancreatic cancer model via the PI3K/AkT/MTOR signaling pathway

Cathepsin K: a unique collagenolytic cysteine peptidase

Papain-like peptidases: structure, function, and evolution

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