An essential feature of cancer is dysregulation of cell senescence and death. Renalase, a recently discovered secreted flavoprotein, provides cytoprotection against ischemic and toxic cellular injury by signaling through the PI3K-AKT and MAPK pathways. Here we show that renalase expression is increased in pancreatic cancer tissue and that it functions as a growth factor. In a cohort of patients with pancreatic ductal adenocarcinoma, overall survival was inversely correlated with renalase expression in the tumor mass, suggesting a pathogenic role for renalase. Inhibition of renalase signaling using siRNA or inhibitory anti-renalase antibodies decreased the viability of cultured pancreatic ductal adenocarcinoma cells. In two xenograft mouse models, either the renalase monoclonal antibody m28-RNLS or shRNA knockdown of renalase inhibited pancreatic ductal adenocarcinoma growth. Inhibition of renalase caused tumor cell apoptosis and cell cycle arrest. These results reveal a previously unrecognized role for the renalase in cancer: its expression may serve as a prognostic maker and its inhibition may provide an attractive therapeutic target in pancreatic cancer.
The reversible regulation of catalytic activity is af eature found in natural enzymes whichi sn ot commonly observed in artificial catalytic systems.H ere,w ef abricate an artificial hydrolase with pH-switchable activity,a chieved by introducing ac atalytic histidine residue at the terminus of apH-responsive peptide.The peptide exhibits aconformational transition from random coil to b-sheet by changing the pH from acidic to alkaline.The b-sheet self-assembles to form long fibrils with the hydrophobic edge and histidine residues extending in an ordered arraya st he catalytic microenvironment, which shows significant esterase activity.C atalytic activity can be reversible switched by pH-induced assembly/ disassembly of the fibrils into random coils.A th igher concentrations,t he peptide forms ah ydrogel whichi sa lso catalytically active and maintains its reversible (de-)activation.
Matrix metalloproteinase (MMP) enzymes
are over-expressed by some
metastatic cancers, in which they are responsible for the degradation
and remodeling of the extracellular matrix. In recent years, MMPs
have emerged as promising targets for enzyme-responsive diagnostic
probes because oligopeptides can be designed to be selectively hydrolyzed
by exposure to these enzymes. With the ultimate goal of developing
radio-iodinated peptides as supramolecular building blocks for MMP-sensitive
tools for nuclear imaging and therapy, we designed three MMP-9-responsive
peptides containing either tyrosine or iodotyrosine to assess the
impact of iodotyrosine introduction to the peptide structure and cleavage
kinetics. We found that the peptides containing iodotyrosine underwent
more rapid and more complete hydrolysis by MMP-9. While the peptides
under investigation were predominantly disordered, it was found that
iodination increased the degree of aromatic residue-driven aggregation
of the peptides. We determined that these iodination-related trends
stem from the improved overall intramolecular order through H- and
halogen bonding, in addition to intermolecular organization of the
self-assembled peptides due to steric and electrostatic effects introduced
by the halogenated tyrosine. These fundamental observations provide
insights for the development of enzyme-triggered peptide aggregation
tools for localized radioactive iodine-based tumor imaging.
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