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serine protease cancer

Blake T Riley, Olga Ilyichova, Mauricio G S Costa, Benjamin T Porebski, Simon J de Veer, Joakim E Swedberg, Itamar Kass, Jonathan M Harris, David E Hoke, Ashley M Buckle
The kallikrein-related peptidase (KLK) family of proteases is involved in many aspects of human health and disease. One member of this family, KLK4, has been implicated in cancer development and metastasis. Understanding mechanisms of inactivation are critical to developing selective KLK4 inhibitors. We have determined the X-ray crystal structures of KLK4 in complex with both sunflower trypsin inhibitor-1 (SFTI-1) and a rationally designed SFTI-1 derivative to atomic (~1 Å) resolution, as well as with bound nickel...
October 21, 2016: Scientific Reports
Rahul Mannan, Tejinder Singh Bhasin, Mridu Manjari, Gagandeep Singh, Puneet Kaur Bhatia, Sonam Sharma
BACKGROUND: Prostate carcinoma is the second leading cause of cancer-related deaths in males worldwide. The burden is expected to grow 1.7 million new cases and 499,000 new deaths by 2030. In developing countries such as India, prostate carcinoma will show an increase by 140% in the next few years. Although the diagnosis of prostate carcinoma can usually be made on histological features, now a days many immunohistochemical (IHC) markers are used to distinguish it from benign mimickers as well as in predicting prognosis and treatment...
October 2016: Indian Journal of Pathology & Microbiology
Caroline M Forrest, Kara McNair, Maria C J Vincenten, L Gail Darlington, Trevor W Stone
BACKGROUND: The related tumour suppressor proteins Deleted in Colorectal Cancer (DCC) and neogenin are absent or weakly expressed in many cancers, whereas their insertion into cells suppresses oncogenic behaviour. Serine proteases influence the initiation and progression of cancers although the mechanisms are unknown. METHODS: The effects of environmental (bacterial subtilisin) and endogenous mammalian (chymotrypsin) serine proteases were examined on protein expression in fresh, normal tissue and human neuroblastoma and mammary adenocarcinoma lines...
October 6, 2016: BMC Cancer
X S Li, X L He
Abnormal expression of the kallikrein (KLK) family of serine proteases closely correlates with onset, progression, and prognosis of endocrine gland-related malignant tumors. The aim of this study was to evaluate how downregulation of KLK12 influenced cell cycle and proliferation of the AGS gastric cancer cell line. KLK12 was detected by western blot in GES-1 normal gastric epithelial and AGS cells. AGS cells were transfected with KLK12 siRNA, a negative control siRNA, or subjected to a mock transfection, following which, we assessed mRNA and protein levels, cell proliferation, cell migration, and cell cycle progression...
August 29, 2016: Genetics and Molecular Research: GMR
Jorge Sandoval-Basilio, Nicolás Serafín-Higuera, Octavio D Reyes-Hernandez, Idanya Serafín-Higuera, Gabriela Leija-Montoya, Magali Blanco-Morales, Monica Sierra-Martínez, Roberto Ramos-Mondragon, Silvia García, Luz Berenice López-Hernández, Martha Yocupicio-Monroy, Sofia L Alcaraz-Estrada
Chromatin in cervical cancer (CC) undergoes chemical and structural changes that alter the expression pattern of genes. Recently, a potential mechanism, which regulates gene expression at transcriptional levels is the proteolytic clipping of histone H3. However, until now this process in CC has not been reported. Using HeLa cells as a model of CC and human samples from patients with CC, we identify that the H3 cleavage was lower in CC compared with control tissue. Additionally, the histone H3 clipping was performed by serine and aspartyl proteases in HeLa cells...
2016: Journal of Cancer
Miguel Angel Sánchez-Garrido, Kirk M Habegger, Christoffer Clemmensen, Cassie Holleman, Timo D Müller, Diego Perez-Tilve, Pengyun Li, Archita S Agrawal, Brian Finan, Daniel J Drucker, Matthias H Tschöp, Richard D DiMarchi, Alexei Kharitonenkov
OBJECTIVE: Fibroblast activation protein (FAP) is a serine protease belonging to a S9B prolyl oligopeptidase subfamily. This enzyme has been implicated in cancer development and recently reported to regulate degradation of FGF21, a potent metabolic hormone. Using a known FAP inhibitor, talabostat (TB), we explored the impact of FAP inhibition on metabolic regulation in mice. METHODS: To address this question we evaluated the pharmacology of TB in various mouse models including those deficient in FGF21, GLP1 and GIP signaling...
October 2016: Molecular Metabolism
Angélique Vétillard, Wafa Bouzid
Animal venoms are complex mixtures containing simple organic molecules, proteins, peptides, and other bioactive elements with extraordinary biological properties associated with their ability to act on a number of molecular receptors in the process of incapacitating their target organisms. In such a context, arthropod venoms are invaluable sources of bioactive substances, with therapeutic interest but the limited availability of some venom such as those from ants, has restricted the potential that these biomolecules could represent...
2016: Biologie Aujourd'hui
Curnis Flavio, Dallatomasina Alice, Mimma Bianco, Anna Gasparri, Angelina Sacchi, Barbara Colombo, Martina Fiocchi, Laura Perani, Massimo Venturini, Carlo Tacchetti, Suvajit Sen, Ricardo Borges, Eleonora Dondossola, Antonio Esposito, Sushil K Mahata, Corti Angelo
Chromogranin A (CgA), a neuroendocrine secretory protein, and its fragments are present in variable amounts in the blood of normal subjects and cancer patients. We investigated whether circulating CgA has a regulatory function in tumor biology and progression. Systemic administration of full-length CgA, but not of fragments lacking the C-terminal region, could reduce tumor growth in murine models of fibrosarcoma, mammary adenocarcinoma, Lewis lung carcinoma, and primary and metastatic melanoma, with U-shaped dose-response curves...
September 24, 2016: Oncotarget
Li-Sheng Zheng, Jun-Ping Yang, Yun Cao, Li-Xia Peng, Rui Sun, Ping Xie, Meng-Yao Wang, Dong-Fang Meng, Dong-Hua Luo, Xiong Zou, Ming-Yuan Chen, Hai-Qiang Mai, Ling Guo, Xiang Guo, Jian-Yong Shao, Bi-Jun Huang, Wei Zhang, Chao-Nan Qian
Nasopharyngeal carcinoma (NPC) has the highest rate of metastasis among head and neck cancers, and distant metastasis is the major reason for treatment failure. The underlying molecular mechanisms of NPC metastasis are not fully understood. Here we report the identification of serine protease inhibitor Kazal-type 6 (SPINK6) as a functional regulator of NPC metastasis via epidermal growth factor receptor (EGFR) signaling. SPINK6 mRNA was upregulated in tumor and highly metastatic NPC cells. Immunohistochemical staining of 534 NPCs revealed elevated SPINK6 expression as an independent unfavorable prognostic factor for overall, disease-free, and distant metastasis-free survival...
September 26, 2016: Cancer Research
Sven O Dahms, John W M Creemers, Yvonne Schaub, Gleb P Bourenkov, Thomas Zögg, Hans Brandstetter, Manuel E Than
Proprotein Convertases (PCs) represent highly selective serine proteases that activate their substrates upon proteolytic cleavage. Their inhibition is a promising strategy for the treatment of cancer and infectious diseases. Inhibitory camelid antibodies were developed, targeting the prototypical PC furin. Kinetic analyses of them revealed an enigmatic non-competitive mechanism, affecting the inhibition of large proprotein-like but not small peptidic substrates. Here we present the crystal structures of furin in complex with the antibody Nb14 and of free Nb14 at resolutions of 2...
September 27, 2016: Scientific Reports
Yu Sun, Namratha Sheshadri, Wei-Xing Zong
Human SERPINB3 and SERPINB4 are evolutionary duplicated serine/cysteine protease inhibitors. Genomic analysis indicates that these paralogous genes were encoded from independent loci arising from tandem gene duplication. Although the two molecules share 92% identity of their amino acid sequences, they are distinct in the Reactive Center Loop (RCL) including a hinge region and catalytic sequences which accounts for altered substrate specificity. Elevated expression of the two molecules have been reported to contribute to numerous pathological conditions such as inflammatory diseases and cancer...
September 13, 2016: Seminars in Cell & Developmental Biology
Mekdes Debela, Viktor Magdolen, Wolfram Bode, Hans Brandstetter, Peter Goettig
Although kallikrein-related peptidase 10 (KLK10) is expressed in a variety of human tissues and body fluids, knowledge of its physiological functions is fragmentary. Similarly, the pathophysiology of KLK10 in cancer is not well understood. In some cancer types, a role as tumor suppressor has been suggested, while in others elevated expression is associated with poor patient prognosis. Active human KLK10 exhibits a unique, three residue longer N-terminus with respect to other serine proteases and an extended 99-loop nearly as long as in tissue kallikrein KLK1...
September 9, 2016: Biological Chemistry
Trevor W Stone, L Gail Darlington, Caroline M Forrest
The serine protease subtilisin induces a form of long-term depression (LTD) which is accompanied by a reduced expression of the axo-dendritic guidance molecule Unco-ordinated-5C (Unc-5C). One objective of the present work was to determine whether a loss of Unc-5C function contributed to subtilisin-induced LTD by using Unc-5C antibodies in combination with the pore-forming agents Triton X-100 (0.005%) or streptolysin O in rat hippocampal slices. In addition we have assessed the effect of subtilisin on the related dependence receptor Deleted in Colorectal Cancer (DCC) and used antibodies to this protein for functional studies...
November 12, 2016: Neuroscience
Jehn-Chuan Lee, Kun-Chun Chiang, Tsui-Hsia Feng, Yu-Jen Chen, Sung-Ting Chuang, Ke-Hung Tsui, Li-Chuan Chung, Horng-Heng Juang
Oral squamous cell carcinoma (OSCC) is a common malignancy with a growing worldwide incidence and prevalence. The N-myc downstream regulated gene (NDRG) family of NDRG1, 2, 3, and mammary serine protease inhibitor (Maspin) gene are well-known modulators in the neoplasia process. Current research has considered iron chelators as new anti-cancer agents; however, the anticancer activities of iron chelators and their target genes in OSCC have not been well investigated. We showed that iron chelators (Dp44mT, desferrioxamine (DFO), and deferasirox) all significantly inhibit SAS cell growth...
2016: International Journal of Molecular Sciences
Daniel E Bassi, Jirong Zhang, Catherine Renner, Andres J Klein-Szanto
Proprotein convertases (PCs) are serine proteases with an active role in the post-translational processing of numerous inactive proteins to active proteins including many substrates of paramount importance in cancer development and progression. Furin (PCSKC3), a well-studied member of this family, is overexpressed in numerous human and experimental malignancies. In the present communication, we treated two furin-overexpressing non-small cell carcinoma (NSCLC) cell lines (Calu-6 and HOP-62) with the PC inhibitor CMK (Decanoyl-Arg-Val-Lys-Arg-chloromethylketone)...
September 1, 2016: Molecular Carcinogenesis
Kvido Strisovsky
Rhomboid-family intramembrane serine proteases are evolutionarily widespread. Their functions in different organisms are gradually being uncovered and already suggest medical relevance for infectious diseases and cancer. In contrast to these advances, selective inhibitors that could serve as efficient tools for investigation of physiological functions of rhomboids, validation of their disease relevance or as templates for drug development are lacking. In this review I extract what is known about rhomboid protease mechanism and specificity, examine the currently used inhibitors, their mechanism of action and limitations, and conclude by proposing routes for future development of rhomboid protease inhibitors...
August 24, 2016: Seminars in Cell & Developmental Biology
Ralph Kettritz
Neutrophil serine proteases (NSPs) exercise tissue-degrading and microbial-killing effects. The spectrum of NSP-mediated functions grows continuously, not least because of methodological progress. Sensitive and specific FRET substrates were developed to study the proteolytic activity of each NSP member. Advanced biochemical methods are beginning to characterize common and specific NSP substrates. The resulting novel information indicates that NSPs contribute not only to genuine inflammatory neutrophil functions but also to autoimmunity, metabolic conditions, and cancer...
September 2016: Immunological Reviews
Hogyoung Kim, Amrita Datta, Sudha Talwar, Sarmad N Saleem, Debasis Mondal, Asim B Abdel-Mageed
Estrogen receptor beta (ERβ) splice variants are implicated in prostate cancer (PC) progression; however their underlying mechanisms remain elusive. We report that non-canonical activation of estradiol (E2)-ERβ2 signaling axis primes growth, colony-forming ability and migration of the androgen receptor (AR)-null castration-resistant PC (CRPC) cells under androgen-deprived conditions (ADC). The non-classical E2-ERβ2 mediates phosphorylation and activation of Src-IGF-1R complex, which in turn triggers p65-dependent transcriptional upregulation of the androgen-regulated serine protease TMPRSS2:ETV5a/TMPRSS2:ETV5b gene fusions under ADC...
August 17, 2016: Oncotarget
Janet C Reid, Nigel C Bennett, Carson R Stephens, Melanie L Carroll, Viktor Magdolen, Judith A Clements, John D Hooper
Kallikrein-related peptidase (KLK) 14 is a serine protease linked to several pathologies including prostate cancer. We show that KLK14 has biphasic effects in vitro on activating and inhibiting components of the prostate cancer associated hepatocyte growth factor (HGF)/Met system. At 5-10 nM KLK14 converts pro-HGF to the two-chain heterodimer required for Met activation, while higher concentrations degrade the HGF α-chain. HGF activator-inhibitor (HAI)-1A and HAI-1B, which inhibit pro-HGF activators, are degraded by KLK14 when protease:inhibitor stoichiometry is 1:1 or the protease is in excess...
August 17, 2016: Biological Chemistry
Justyna Sosna, Stephan Philipp, Johaiber Fuchslocher Chico, Carina Saggau, Jürgen Fritsch, Alexandra Föll, Johannes Plenge, Christoph Arenz, Thomas Pinkert, Holger Kalthoff, Anna Trauzold, Ingo Schmitz, Stefan Schütze, Dieter Adam
Recently, a type of regulated necrosis (RN) called necroptosis was identified to be involved in many pathophysiological processes and emerged as an alternative method to eliminate cancer cells. However, only a few studies have elucidated components of TRAIL-mediated necroptosis useful for anticancer therapy. Therefore, we have compared this type of cell death to tumor necrosis factor (TNF)-mediated necroptosis and found similar signaling through acid and neutral sphingomyelinases, the mitochondrial serine protease HtrA2/Omi, Atg5, and vacuolar H(+)-ATPase...
October 15, 2016: Molecular and Cellular Biology
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