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serine protease cancer

Larissa Dettmar, Nancy Ahmed, Matthias Kotzsch, Sandra Diersch, Rudolf Napieralski, Dalila Darmoul, Manfred Schmitt, Wilko Weichert, Marion Kiechle, Julia Dorn, Viktor Magdolen
PURPOSE: Gene expression of a variety of the 15 members of the KLK serine protease family is dysregulated in ovarian cancer. We aimed at determining the clinical relevance of KLK13 and KLK14 mRNA expression in tumor tissues of a homogeneous patient cohort afflicted with advanced high-grade serous ovarian cancer (FIGO stage III/IV). METHODS: mRNA expression levels of KLK13 and KLK14 were assessed by quantitative PCR in tumor tissue of 91 patients and related with clinical factors and patients' outcome...
March 15, 2018: Journal of Cancer Research and Clinical Oncology
Chien-Liang Liu, Po-Sheng Yang, Ming-Nan Chien, Yuan-Ching Chang, Chi-Hsin Lin, Shih-Ping Cheng
SPINT1, also known as HAI-1, is a Kunitz-type serine protease inhibitor that inhibits multiple proteases including hepatocyte growth factor (HGF) activator and matriptase. SPINT1 has been shown to modulate HGF/MET activation in certain cancer types. In the present study, we analyzed microarray datasets and found that SPINT1 was consistently upregulated in differentiated thyroid cancer. SPINT1 protein expression was investigated using tissue microarrays and independent samples of our 143 patients. Strong SPINT1 expression was observed in 61-68% of papillary thyroid cancer and 41-50% of follicular thyroid cancer...
March 12, 2018: Histochemistry and Cell Biology
Trevor W Stone, Megan McPherson, L Gail Darlington
Existing explanations of obesity-associated cancer emphasise direct mutagenic effects of dietary components or hormonal imbalance. Some of these hypotheses are reviewed briefly, but recent evidence suggests a major role for chronic inflammation in cancer risk, possibly involving dietary content. These ideas include the inflammation-induced activation of the kynurenine pathway and its role in feeding and metabolism by activation of the aryl hydrocarbon receptor (AHR) and by modulating synaptic transmission in the brain...
February 27, 2018: EBioMedicine
A M Rose, A Krishan, C F Chakarova, L Moya, S Chambers, M Hollands, J C Illingworth, S M G Williams, H E James, A Z Shah, C N A Palmer, A Chakravarti, J N Berg, J Batra, S S Bhattacharya
Background: MSR1 repeats are a 36-38bp minisatellite element that have recently been implicated in the regulation of gene expression, through copy number variation (CNV). Patients and methods: Bioinformatic and experimental methods were used to assess the distribution of MSR1 across the genome, evaluate the regulatory potential of such elements and explore the role of MSR1 elements in cancer, particularly non-familial breast cancer and prostate cancer. Results: MSR1s are predominately located at chromosome 19 and are functionally enriched in regulatory regions of the genome, particularly regions implicated in short-range regulatory activities (H3K27ac, H3K4me1, and H3K4me3)...
March 2, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Mohammad Ali, Edward S Mocarski
Proteasome inhibitors have achieved clinical success because they trigger intrinsic and extrinsic cell death to eliminate susceptible human cancers. The ubiquitin-proteasome protein degradation system regulates signaling pathways by controlling levels of components such as cellular inhibitor of apoptosis (cIAP)1 and cIAP2 in TNF-mediated cell death. Here, we sought to evaluate the contribution of necroptosis to the cell death pattern induced by the specific proteasome inhibitor Carfilzomib (Cf). Proteasome inhibitor-sensitive multiple myeloma cell lines die in response to Cf by apoptosis in combination with serine protease-dependent death, without any contribution of RIPK3-dependent necroptosis...
March 1, 2018: Cell Death & Disease
Elisabetta Falvo, Francesca Malagrinò, Alessandro Arcovito, Francesco Fazi, Gianni Colotti, Elisa Tremante, Patrizio Di Micco, Aldo Braca, Roberta Opri, Alessandro Giuffrè, Giulio Fracasso, Pierpaolo Ceci
A genetically engineered human ferritin heavy chain (HFt)-based construct has been recently shown by our group to efficiently entrap and deliver doxorubicin to cancer cells. This construct, named HFt-MP-PAS, contained a tumor-selective sequence (MP) responsive to proteolytic cleavage by tumor proteases (MMPs), located between each HFt subunit and an outer shielding polypeptide sequence rich in proline (P), serine (S) and alanine (A) residues (PAS). HFt-MP-PAS displayed excellent therapeutic efficacy in xenogenic pancreatic and head and neck cancer models in vivo, leading to a significant increase in overall animal survivals...
February 20, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Xiguang Zhang, Jean Yves Brossas, Christophe Parizot, Jean Marc Zini, Angelita Rebollo
Cell penetrating peptides (CPP) are able cross the membrane and to transport cargos, presenting a great potential in drug delivery and diagnosis. In this paper, we have identified novel natural or synthetic CPPs. We have validated their rapid and efficient time and dose-dependent penetration, the absence of toxicity, the intracellular localization and the stability to proteases degradation, one of the main bottlenecks of peptides. Moreover, we have associate a cargo (an interfering peptide blocking the association of the serine/threonine phosphatase PP2A to its inhibitor, the oncogene SET) to the new generated shuttles and showed that they new bi-functional peptides keep the original properties of the shuttle and, in addition, are able to induce apoptosis due to the properties of the cargo...
January 19, 2018: Oncotarget
Yaowu He, Janet C Reid, Brittney S Harrington, Brittney Finlayson, Tashbib Khan, John D Hooper
The cellular receptor CUB Domain Containing Protein 1 (CDCP1) is commonly elevated and functionally important in a range of cancers. CDCP1 is cleaved by serine proteases at adjacent sites, arginine 368 (R368) and lysine 369 (K369), which induces cell migration in vitro, and metastasis in vivo. We demonstrate that membrane localization of serine protease activity increases efficacy of cleavage of CDCP1, and that both secreted and membrane anchored serine proteases can have distinct preferences for cleaving at CDCP1-R368 and -K369...
November 27, 2017: Biological Chemistry
Shengyun Cai, Pei Zhang, Suhe Dong, Li Li, Jianming Cai, Mingjuan Xu
BACKGROUND/AIMS: Ovarian cancer (OC) is the fifth leading cause of cancer-related death in women, and it is difficult to diagnose at an early stage. The purpose of this study was to explore the prognostic biological markers of OC. METHODS: Univariate Cox regression analysis was used to identify genes related to OC prognosis from the Cancer Genome Atlas(TCGA) database. Immunohistochemistry was used to analyse the level of SPINK13 in OC and normal tissues. Cell proliferation, apoptosis and invasion were performed using MTT assay, flow cytometric analysis and Transwell assay, respectively...
February 7, 2018: Cellular Physiology and Biochemistry
Hiroaki Kataoka, Makiko Kawaguchi, Tsuyoshi Fukushima, Takeshi Shimomura
The growth, survival, and metabolic activities of multicellular organisms at the cellular level are regulated by intracellular signaling, systemic homeostasis and the pericellular microenvironment. Pericellular proteolysis has a crucial role in processing bioactive molecules in the microenvironment and thereby has profound effects on cellular functions. Hepatocyte growth factor activator inhibitor type 1 (HAI-1) and HAI-2 are type I transmembrane serine protease inhibitors expressed by most epithelial cells...
February 12, 2018: Pathology International
Andrew B Fielding, Matthew Concannon, Sarah Darling, Emma V Rusilowicz-Jones, Joseph J Sacco, Ian A Prior, Michael J Clague, Sylvie Urbé, Judy M Coulson
Ubiquitin-specific protease 15 (USP15) is a widely expressed deubiquitylase that has been implicated in diverse cellular processes in cancer. Here we identify topoisomerase II (TOP2A) as a novel protein that is regulated by USP15. TOP2A accumulates during G2 and functions to decatenate intertwined sister chromatids at prophase, ensuring the replicated genome can be accurately divided into daughter cells at anaphase. We show that USP15 is required for TOP2A accumulation, and that USP15 depletion leads to the formation of anaphase chromosome bridges...
February 12, 2018: Oncogene
Julie Brogaard Larsen, Anne Troldborg, Thomas Decker Christensen, Christine Lodberg Hvas, Steffen Thiel, Anne-Mette Hvas
BACKGROUND: Lectin pathway proteases activate coagulation and may theoretically play a role in the increased thrombosis risk in cancer, which is especially high during surgery. AIMS: To investigate lectin pathway proteins during lung cancer surgery, the influence of low molecular weight heparin (LMWH) on lectin pathway proteins, and correlations between lectin pathway proteins and coagulation. METHODS: Fifty lung cancer patients undergoing video-assisted thoracoscopic surgery lobectomy were randomised to LMWH, n = 26, or no anticoagulant (control), n = 24...
January 30, 2018: Thrombosis Research
Fatma H Al-Awadhi, Valerie J Paul, Hendrik Luesch
Three new 3-amino-6-hydroxy-2-piperidone (Ahp)-containing cyclic depsipeptides named loggerpeptins A-C (1-3) along with molassamide (4) were discovered from a marine cyanobacterium, extending the structural diversity of this prevalent scaffold of cyanobacterial serine protease inhibitors. Molassamide (4), containing the 2-amino-butenoic (Abu) unit in the cyclic core, was the most potent and selective analogue against human neutrophil elastase (HNE). Given the growing evidence supporting the role of HNE in breast cancer progression and metastasis, we assessed the cellular effects of compounds 3 and 4 in the context of targeting invasive breast cancer...
February 5, 2018: Chembiochem: a European Journal of Chemical Biology
Marian C Okondo, Sahana D Rao, Cornelius Y Taabazuing, Ashley J Chui, Sarah E Poplawski, Darren C Johnson, Daniel A Bachovchin
Val-boroPro (PT-100, Talabostat) induces powerful anti-tumor immune responses in syngeneic cancer models, but its mechanism of action has not yet been established. Val-boroPro is a non-selective inhibitor of post-proline-cleaving serine proteases, and the inhibition of the highly related cytosolic serine proteases Dpp8 and Dpp9 (Dpp8/9) by Val-boroPro was recently demonstrated to trigger an immunostimulatory form of programmed cell death known as pyroptosis selectively in monocytes and macrophages. Here we show that Dpp8/9 inhibition activates the inflammasome sensor protein Nlrp1b, which in turn activates pro-caspase-1 to mediate pyroptosis...
January 26, 2018: Cell Chemical Biology
Mariana T Q de Magalhães, Fábio S Mambelli, Bruno P O Santos, Suellen B Morais, Sergio C Oliveira
Proteins containing a Kunitz domain have the typical serine protease inhibition function ranging from sea anemone to man. Protease inhibitors play major roles in infection, inflammation disorders and cancer. This review discusses the role of serine proteases containing a Kunitz domain in immunomodulation induced by helminth parasites. Helminth parasites are associated with protection from inflammatory conditions. Therefore, interest has raised whether worm parasites or their products hold potential as drugs for treatment of immunological disorders...
January 18, 2018: Microbes and Infection
Tatiana Goretsky, Emily M Bradford, Qing Ye, Olivia F Lamping, Tomas Vanagunas, Mary Pat Moyer, Patrick C Keller, Preetika Sinh, Josep M Llovet, Tianyan Gao, Qing-Bai She, Linheng Li, Terrence A Barrett
Nuclear activation of Wnt/β-catenin signaling is required for cell proliferation in inflammation and cancer. Studies from our group indicate that β-catenin activation in colitis and colorectal cancer (CRC) correlates with increased nuclear levels of β-catenin phosphorylated at serine 552 (pβ-Cat552). Biochemical analysis of nuclear extracts from cancer biopsies revealed the existence of low molecular weight (LMW) pβ-Cat552, increased to the exclusion of full size (FS) forms of β-catenin. LMW β-catenin lacks both termini, leaving residues in the armadillo repeat intact...
January 12, 2018: Scientific Reports
Shishir M Pant, Denis Belitskin, Hanna Ala-Hongisto, Juha Klefström, Topi A Tervonen
Breakdown of the basement membrane is a key step that precedes tumor invasion, and accumulating evidence suggests a key role for the type II transmembrane proteases (TTSPs) in that process. Overexpression of a TTSP hepsin characterizes many solid cancers, including prostate, breast, and ovarian cancer, and in experimental tumor models, the elevated proteolytic activity of hepsin simultaneously activates several growth factors and cleaves basement membrane protein laminin-332, which is an essential component of the cell-basement membrane junction hemidesmosome...
2018: Methods in Molecular Biology
Angela Moncada-Pazos, Adam Graham Grieve
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...
2018: Methods in Molecular Biology
Sven O Dahms, Kornelia Hardes, Torsten Steinmetzer, Manuel E Than
The proprotein convertase (PC) furin is a highly specific serine protease modifying and thereby activating proteins in the secretory pathway by proteolytic cleavage. Its substrates are involved in many diseases including cancer and infections caused by bacteria and viruses. Understanding furin's substrate specificity is of crucial importance for the development of pharmacologically applicable inhibitors. Using protein X-ray crystallography we investigated the extended substrate binding site of furin in complex with three peptide derived inhibitors at up to 1...
January 9, 2018: Biochemistry
Aldo Bonaventura, Luca Liberale, Federico Carbone, Alessandra Vecchié, Candela Diaz-Cañestro, Giovanni G Camici, Fabrizio Montecucco, Franco Dallegri
Neutrophil pathogen-killing mechanism termed neutrophil extracellular traps (NETs) has been recently identified. NETs consist of chromatin and histones along with serine proteases and myeloperoxidase and are induced by a great variety of infectious and non-infectious stimuli . NETosis is a kind of programmed neutrophil death characterized by chromatin decondensation and release of nuclear granular contents, mainly driven by peptidylarginine deiminase 4 citrullination of histones. Although classically related to the protection against infectious pathogens, nowadays NETs have been described as a player of several pathophysiological processes...
January 2018: Thrombosis and Haemostasis
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