scholarly journals Type II transmembrane serine proteases as potential targets for cancer therapy

2016 ◽  
Vol 397 (9) ◽  
pp. 815-826 ◽  
Author(s):  
Andrew S. Murray ◽  
Fausto A. Varela ◽  
Karin List
Keyword(s):  
Cancer Progression ◽  
Serine Proteases ◽  
Molecular Mechanisms ◽  
Inflammatory Cells ◽  
Activity Levels ◽  
Type Ii ◽  
Neoplastic Progression ◽  
Treatment Regimens ◽  
Proinflammatory Mediators ◽  
Transmembrane Serine Protease

Abstract Carcinogenesis is accompanied by increased protein and activity levels of extracellular cell-surface proteases that are capable of modifying the tumor microenvironment by directly cleaving the extracellular matrix, as well as activating growth factors and proinflammatory mediators involved in proliferation and invasion of cancer cells, and recruitment of inflammatory cells. These complex processes ultimately potentiate neoplastic progression leading to local tumor cell invasion, entry into the vasculature, and metastasis to distal sites. Several members of the type II transmembrane serine protease (TTSP) family have been shown to play critical roles in cancer progression. In this review the knowledge collected over the past two decades about the molecular mechanisms underlying the pro-cancerous properties of selected TTSPs will be summarized. Furthermore, we will discuss how these insights may facilitate the translation into clinical settings in the future by specifically targeting TTSPs as part of novel cancer treatment regimens.

scholarly journals Phenotypic Analysis of Mice Lacking the Tmprss2-Encoded Protease

2006 ◽  
Vol 26 (3) ◽  
pp. 965-975 ◽  
Author(s):  
Tom S. Kim ◽  
Cynthia Heinlein ◽  
Robert C. Hackman ◽  
Peter S. Nelson
Keyword(s):  
Serine Protease ◽  
Serine Proteases ◽  
Biological Activities ◽  
Type Ii ◽  
Phenotypic Analysis ◽  
Normal Prostate ◽  
Prostate Hyperplasia ◽  
Transmembrane Serine Protease

ABSTRACT Tmprss2 encodes an androgen-regulated type II transmembrane serine protease (TTSP) expressed highly in normal prostate epithelium and has been implicated in prostate carcinogenesis. Although in vitro studies suggest protease-activated receptor 2 may be a substrate for TMPRSS2, the in vivo biological activities of TMPRSS2 remain unknown. We generated Tmprss2 −/− mice by disrupting the serine protease domain through homologous recombination. Compared to wild-type littermates, Tmprss2 −/− mice developed normally, survived to adulthood with no differences in protein levels of prostatic secretions, and exhibited no discernible abnormalities in organ histology or function. Loss of TMPRSS2 serine protease activity did not influence fertility, reduce survival, result in prostate hyperplasia or carcinoma, or alter prostatic luminal epithelial cell regrowth following castration and androgen replacement. Lack of an observable phenotype in Tmprss2 −/− mice was not due to transcriptional compensation by closely related Tmprss2 homologs. We conclude that the lack of a discernible phenotype in Tmprss2 −/− mice suggests functional redundancy involving one or more of the type II transmembrane serine protease family members or other serine proteases. Alternatively, TMPRSS2 may contribute a specialized but nonvital function that is apparent only in the context of stress, disease, or other systemic perturbation.

TMPRSS4 is a type II transmembrane serine protease involved in cancer and viral infections

2012 ◽  
Vol 393 (9) ◽  
pp. 907-914 ◽  
Author(s):  
Anke Ohler ◽  
Christoph Becker-Pauly
Keyword(s):  
Serine Protease ◽  
Serine Proteases ◽  
Viral Infections ◽  
Proteolytic Enzymes ◽  
Metastatic Potential ◽  
Influenza Viruses ◽  
Type Ii ◽  
Serine Protease Family ◽  
Transmembrane Serine Protease ◽  
Almost All

Abstract Proteolytic enzymes are involved in almost all biological processes reflecting their importance in health and disease. The human genome contains nearly 600 protease-encoding genes forming more than 2% of the total human proteome. The serine proteases, with about 180 members, built the oldest and second largest family of human proteases. Ten years ago, a novel serine protease family named the type II transmembrane family (TTSP) was identified. This minireview summarizes the up-to-date knowledge about the still growing TTSPs, particularly focusing on the pathophysiological functions of the family member type II transmembrane serine protease (TMPRSS) 4. Recent studies provided important data on TMPRSS4 activity associated with the spreading of influenza viruses, mediated by the cleavage of hemagglutinin. Progression and metastatic potential of several cancers is concordant with an increased expression of TMPRSS4, though being a possible diagnostic marker. However, to benefit from TMPRSS4 as a therapeutic target, more data concerning its physiological relevance are needed, as done by a specific morpholino knockdown in zebrafish embryos.

scholarly journals Matriptase-Induced Phosphorylation of MET is Significantly Associated with Poor Prognosis in Invasive Bladder Cancer; an Immunohistochemical Analysis

2018 ◽  
Vol 19 (12) ◽  
pp. 3708 ◽  
Author(s):  
Koji Yamasaki ◽  
Shoichiro Mukai ◽  
Takahiro Nagai ◽  
Kozue Nakahara ◽  
Masato Fujii ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Progression ◽  
Poor Prognosis ◽  
Immunohistochemical Analysis ◽  
High Expression ◽  
Invasive Bladder Cancer ◽  
Type Ii ◽  
Hgf Activator ◽  
Transmembrane Serine Protease ◽  
Hepatocyte Growth

Hepatocyte growth factor (HGF) plays an important role in cancer progression via phosphorylation of MET (c-met proto-oncogene product, receptor of HGF). HGF-zymogen (pro-HGF) must be processed for activation by HGF activators including matriptase, which is a type II transmembrane serine protease and the most efficient activator. The enzymatic activity is tightly regulated by HGF activator inhibitors (HAIs). Dysregulated pro-HGF activation (with upregulated MET phosphorylation) is reported to promote cancer progression in various cancers. We retrospectively analyzed the expression of matriptase, phosphorylated-MET (phospho-MET) and HAI-1 in tumor specimens obtained from patients with invasive bladder cancer by immunohistochemistry. High expression of phospho-MET and increased expression of matriptase were significantly associated with poor prognosis, and high matriptase/low HAI-1 expression showed poorer prognosis. Furthermore, high expression of matriptase tended to correlate with phosphorylation of MET. Increased expression of matriptase may induce the ligand-dependent activation of MET, which leads to poor prognosis in patients with invasive bladder cancer.

Genetic Interactions Between the RhoA and Stubble-stubbloid Loci Suggest a Role for a Type II Transmembrane Serine Protease in Intracellular Signaling During Drosophila Imaginal Disc Morphogenesis

Genetics ◽  
2003 ◽  
Vol 165 (3) ◽  
pp. 1417-1432 ◽  
Author(s):  
Cynthia A Bayer ◽  
Susan R Halsell ◽  
James W Fristrom ◽  
Daniel P Kiehart ◽  
Laurence von Kalm
Keyword(s):  
Serine Protease ◽  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Serine Proteases ◽  
Imaginal Discs ◽  
Type Ii ◽  
Gene Encoding ◽  
Developmental Abnormalities ◽  
Transmembrane Serine Protease ◽  
Rhoa Signaling

Abstract The Drosophila RhoA (Rho1) GTPase is essential for postembryonic morphogenesis of leg and wing imaginal discs. Mutations in RhoA enhance leg and wing defects associated with mutations in zipper, the gene encoding the heavy chain of nonmuscle myosin II. We demonstrate here that mutations affecting the RhoA signaling pathway also interact genetically with mutations in the Stubble-stubbloid (Sb-sbd) locus that encodes an unusual type II transmembrane serine protease required for normal leg and wing morphogenesis. In addition, a leg malformation phenotype associated with overexpression of Sb-sbd in prepupal leg discs is suppressed when RhoA gene dose is reduced, suggesting that RhoA and Sb-sbd act in a common pathway during leg morphogenesis. We also characterized six mutations identified as enhancers of zipper mutant leg defects. Three of these genes encode known members of the RhoA signaling pathway (RhoA, DRhoGEF2, and zipper). The remaining three enhancer of zipper mutations interact genetically with both RhoA and Sb-sbd mutations, suggesting that they encode additional components of the RhoA signaling pathway in imaginal discs. Our results provide evidence that the type II transmembrane serine proteases, a class of proteins linked to human developmental abnormalities and pathology, may be associated with intracellular signaling required for normal development.

scholarly journals Using Mouse and Drosophila Models to Investigate the Mechanistic Links between Diet, Obesity, Type II Diabetes, and Cancer

2018 ◽  
Vol 19 (12) ◽  
pp. 4110 ◽  
Author(s):  
Coral Warr ◽  
Katherine Shaw ◽  
Arani Azim ◽  
Matthew Piper ◽  
Linda Parsons
Keyword(s):  
Cancer Progression ◽  
Type Ii Diabetes ◽  
Molecular Mechanisms ◽  
Genetic Manipulation ◽  
Growth Factor Signaling ◽  
Type Ii ◽  
Cancer Models ◽  
Increased Risk ◽  
Diet And Cancer ◽  
Risk Of Cancer

Many of the links between diet and cancer are controversial and over simplified. To date, human epidemiological studies consistently reveal that patients who suffer diet-related obesity and/or type II diabetes have an increased risk of cancer, suffer more aggressive cancers, and respond poorly to current therapies. However, the underlying molecular mechanisms that increase cancer risk and decrease the response to cancer therapies in these patients remain largely unknown. Here, we review studies in mouse cancer models in which either dietary or genetic manipulation has been used to model obesity and/or type II diabetes. These studies demonstrate an emerging role for the conserved insulin and insulin-like growth factor signaling pathways as links between diet and cancer progression. However, these models are time consuming to develop and expensive to maintain. As the world faces an epidemic of obesity and type II diabetes we argue that the development of novel animal models is urgently required. We make the case for Drosophila as providing an unparalleled opportunity to combine dietary manipulation with models of human metabolic disease and cancer. Thus, combining diet and cancer models in Drosophila can rapidly and significantly advance our understanding of the conserved molecular mechanisms that link diet and diet-related metabolic disorders to poor cancer patient prognosis.

scholarly journals The role of lysosomal cysteine proteases in tumor progression

2009 ◽  
Vol 8 (2) ◽  
pp. 85-90
Author(s):  
M. S. Korovin ◽  
V. V. Novitsky ◽  
O. S. Vasiliyeva
Keyword(s):  
Tumor Progression ◽  
Cancer Progression ◽  
Serine Proteases ◽  
Molecular Mechanisms ◽  
Cysteine Proteases ◽  
Tumour Microenvironment ◽  
Cysteine Cathepsins ◽  
Proteolytic Cascade ◽  
Long Time ◽  
Lysosomal Cysteine Proteases

Cysteine cathepsins have been known for a long time to play an important role in cancer progression. Here we summarize their impact to the hallmark processes of malignant growth such as cell proliferation, apoptosis, angiogenesis, invasion and metastasis. We discuss the molecular mechanisms where cysteine cathepsins are participating through the degradation of the extracellular matrix, initiation of the proteolytic cascade by activating serine proteases and urokinase plasminogen precursors. Moreover, in addition to the tumorigenic and pro-metastatic functions of lysosomal cysteine proteases in the cancer cells, cathepsins originating from cells of the tumour microenvironment has been shown to participate in the processes leading to the tumor progression and metastasis. Taken together, that data support the concept of cysteine cathepsins as promising molecular targets for cancer therapy.

Purines and Pyrimidines: Metabolism, Function and Potential as therapeutic options in neurodegenerative diseases

2020 ◽  
Vol 21 ◽  
Author(s):  
Debanjan Kundu ◽  
Vikash Kumar Dubey
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Treatment Regimens ◽  
Loss Of Balance ◽  
Current Scenario ◽  
Unexplored Area ◽  
Molecular Origin ◽  
Purines And Pyrimidines

Abstract:: Various neurodegenerative disorders have molecular origin but some common molecular mechanisms. In the current scenario, there are very few treatment regimens present for advanced neurodegenerative diseases. In this context, there is an urgent need for alternate options in the form of natural compounds with an ameliorating effect on patients. There have been individual scattered experiments trying to identify potential values of various intracellular metabolites. Purines and Pyrimidines, which are vital molecules governing various aspects of cellular biochemical reactions, have been long sought as crucial candidates for the same, but there are still many questions that go unanswered. Some critical functions of these molecules associated with neuromodulation activities have been identified. They are also known to play a role in foetal neurodevelopment, but there is a lacuna in understanding their mechanisms. In this review, we have tried to assemble and identify the importance of purines and pyrimidines, connecting them with the prevalence of neurodegenerative diseases. The leading cause of this class of diseases is protein misfolding and the formation of amyloids. A direct correlation between loss of balance in cellular homeostasis and amyloidosis is yet an unexplored area. This review aims at bringing the current literature available under one umbrella serving as a foundation for further extensive research in this field of drug development in neurodegenerative diseases.

Novel Findings of Anti-cancer Property of Propofol

2018 ◽  
Vol 18 (2) ◽  
pp. 156-165 ◽  
Author(s):  
Jiaqiang Wang ◽  
Chien-shan Cheng ◽  
Yan Lu ◽  
Xiaowei Ding ◽  
Minmin Zhu ◽  
...  
Keyword(s):  
General Anesthesia ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Intravenous Anesthetic ◽  
The Past ◽  
Anti Cancer ◽  
Underlying Mechanisms ◽  
Recent Attention

Background: Propofol, a widely used intravenous anesthetic agent, is traditionally applied for sedation and general anesthesia. Explanation: Recent attention has been drawn to explore the effect and mechanisms of propofol against cancer progression in vitro and in vivo. Specifically, the proliferation-inhibiting and apoptosis-inducing properties of propofol in cancer have been studied. However, the underlying mechanisms remain unclear. Conclusion: This review focused on the findings within the past ten years and aimed to provide a general overview of propofol's malignance-modulating properties and the potential molecular mechanisms.

Sign in / Sign up

Export Citation Format

Share Document