Prevention of prostate‐cancer metastasis in vivo by a novel synthetic inhibitor of urokinase‐type plasminogen activator (uPA)

1995 ◽  
Vol 63 (6) ◽  
pp. 840-845 ◽  
Author(s):  
Shafaat Rabbani ◽  
Penelope Harakidas ◽  
Donald J. Davidson ◽  
Jack Henkin ◽  
Andrew P. Mazar
Keyword(s):  
Prostate Cancer ◽  
Plasminogen Activator ◽  
Cancer Metastasis ◽  
Synthetic Inhibitor ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Prostate Cancer Metastasis

scholarly journals Constriction of carotid arteries by urokinase-type plasminogen activator requires catalytic activity and is independent of NH2-terminal domains

2009 ◽  
Vol 102 (11) ◽  
pp. 983-992 ◽  
Author(s):  
Philip Massey ◽  
Shinji Tanaka ◽  
Joshua Buckler ◽  
Bo Jiang ◽  
Anton McCourtie ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Plasminogen Activator ◽  
Carotid Arteries ◽  
Artery Wall ◽  
Kringle Domains ◽  
Type Plasminogen Activator ◽  
Endothelial Surface ◽  
Urokinase Type Plasminogen Activator ◽  
Human Arteries

SummaryUrokinase-type plasminogen activator (uPA) is expressed at increased levels in stenotic, atherosclerotic human arteries. However, the biological roles of uPA in the artery wall are poorly understood. Previous studies associate uPA with both acute vasoconstriction and chronic vascular remodeling and attribute uPA-mediated vasoconstriction to the kringle – not the catalytic domain of uPA. We used an in-vivo uPA overexpression model to test the hypothesis that uPA-induced vasoconstriction is a reversible vasomotor process that can be prevented – and uPA fibrinolytic activity preserved – by: 1) removing the growth factor and kringle domains; or 2) anchoring uPA to the endothelial surface. To test this hypothesis we constructed adenoviral vectors that express: wild-type rabbit uPA (AduPA); a uPA mutant lacking the NH2-terminal growth-factor and kringle domains (Adu-PAdel); a mutant lacking catalytic activity (AduPAS→A), and a cell-surface anchored mutant (AdTMuPA). uPA mutants were expressed and characterised in vitro and in carotid arteries in vivo. uPAS→A had no plasminogen activator activity. Activity was similar for uPA and uPAdel, whereas AdTMuPA had only cell-associated activity. AduPAS→A arteries were not constricted. AduPA, AduPAdel, and AdTM-uPA arteries were constricted (approximately 30% smaller lumens; p≤0.008 vs. AdNull arteries). Papaverine reversed constriction of AduPA arteries. uPA-mediated arterial constriction is a vasomotor process that is mediated by uPA catalytic activity, not by the NH2-terminal domains. Anchoring uPA to the endothelial surface does not prevent vasoconstriction. uPA catalytic activity, generated by artery wall cells, may contribute to lumen loss in human arteries. Elimination of uPA vasoconstrictor activity requires concomitant loss of fibrinolytic activity.

ON THE MECHANISM OF THE IN VIVO SYNERGISM BETWEEN TISSUE-TYPE PLASMINOGEN ACTIVATOR (t-PA) AND SINGLE CHAIN UROKINASE-TYPE PLASMINOGEN ACTIVATOR (scu-PA)

1987 ◽  
Author(s):  
J M Stassen ◽  
D Collen
Keyword(s):  
Plasminogen Activator ◽  
Rabbit Model ◽  
Sequential Therapy ◽  
Tissue Type ◽  
Single Chain ◽  
Molar Ratios ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator

t-PA and scu-PA, in molar ratios between 1:4 and 4:1 do not act synergically in vitro (Thromb. Haemost. 56,35,1986) but display marked synergism in a rabbit model (Circulation 74, 838, 1986) and in man (Am. Heart J. 112, 1083, 1986). To investigate the mechanism of in vivo synergism in the rabbit model (J. Clin. Invest. 71, 368, 1983), t-PA and scu-PA were infused 1) simultaneously over 4 hrs, 2) t-PA over 1 hr, then 15 min later scu-PA over 2 hrs and 3) scu-PA over 1 hr, then 15 min later t-PA over 2 hrs.Significant synergism on thrombolysis is observed when t-PA and scu-PA are infused simultaneously or when t-PA is followed by scu-PA but not when scu-PA is followed by t-PA. These results suggest that low dose t-PA induces some plasminogen activation, sufficient to partially degrade fibrin, exposing COOH-terminal lysines with high affinity for plasminogen (Eur. J. Biochem. 140, 513, 1984). scu-PA might then activate surface-bound Glu-pla-minogen more efficiently.Sequential therapy with t-PA (or any other agent which "predigests" the thrombus), followed by scu-PA might constitute an alternative to simultaneous infusion of synergistic thrombolytic agents.

Sometimes a cigar is just a cigar

Blood ◽  
2010 ◽  
Vol 116 (9) ◽  
pp. 1394-1395
Author(s):  
Shih-Hon Li ◽  
Daniel A. Lawrence
Keyword(s):  
Plasminogen Activator ◽  
Molecular Interactions ◽  
Mouse Strain ◽  
Mutant Form ◽  
Primary Role ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator

In this issue of Blood, Connolly and colleagues describe an elegant approach to studying the significance of specific molecular interactions in vivo. The authors have “knocked-in” a mutant form of the protease, urokinase-type plasminogen activator (uPA), into the murine uPA locus, to create a mouse strain (PlauGFDhu/GFDhu) where the interaction between endogenous uPA and its receptor (uPAR) is selectively disrupted, while leaving other functions of both uPA and uPAR intact. Their findings suggest that the primary role of uPAR in vivo is to promote fibrinolysis within tissues through localization of uPA, and that many of the previously described activities of uPAR may be secondary to this process.1

scholarly journals Activation of hepatocyte growth factor by urokinase-type plasminogen activator is ionic strength-dependent

2005 ◽  
Vol 390 (1) ◽  
pp. 311-315 ◽  
Author(s):  
Wendy M. Mars ◽  
Minji Jo ◽  
Steven L. Gonias
Keyword(s):  
Ionic Strength ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Molecular Mass ◽  
Plasminogen Activator ◽  
Tissue Type ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Hepatocyte Growth

The hepatocyte growth factor (HGF) is a multifunctional cytokine that is produced as latent scHGF (single chain HGF). Various proteases reportedly cleave scHGF to generate the active two-chain form (HGF), including u-PA (urokinase-type plasminogen activator), t-PA (tissue-type plasminogen activator), kallikrein, Factor XIa, Factor XIIa, HGF activator and matriptase. Considerable evidence indicates that, in vivo, u-PA activates scHGF in the liver; however, the in vivo results have not been uniformly supported by in vitro experiments. We now report that cleavage of scHGF by high-molecular-mass u-PA (abbreviated u-PA throughout) is sensitive to ionic strength. scHGF cleavage by u-PA was accelerated as the ionic strength was decreased. This result was equivalent irrespective of whether the predominant anion was chloride or acetate. Lmw-u-PA (low-molecular-mass u-PA) was ineffective at cleaving scHGF, regardless of ionic strength. Although scHGF shares homology with plasminogen, EACA (ϵ-amino-caproic acid) did not regulate u-PA-mediated scHGF cleavage. Soluble HGF receptor (MET) and soluble u-PAR (u-PA receptor) inhibited the scHGF cleavage. These results support a model in which the ability of u-PA to activate scHGF in vivo may be highly dependent on local conditions within the extracellular space.

scholarly journals RIPK2 Stabilizes c-Myc and is an Actionable Target for Inhibiting Prostate Cancer Metastasis

2020 ◽  
Author(s):  
Yiwu Yan ◽  
Bo Zhou ◽  
Chen Qian ◽  
Alex Vasquez ◽  
Avradip Chatterjee ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Drug Targets ◽  
Cancer Metastasis ◽  
Therapeutic Interventions ◽  
Interacting Protein ◽  
Prostate Cancer Metastasis ◽  
Prostate Cancers

AbstractDespite advances in diagnosis and treatment, metastatic prostate cancer remains incurable and is associated with high mortality rates. Thus, novel actionable drug targets are urgently needed for therapeutic interventions in advanced prostate cancer. Here we report receptor-interacting protein kinase 2 (RIPK2) as an actionable drug target for suppressing prostate cancer metastasis. RIPK2 is frequently amplified in lethal prostate cancers and its overexpression is associated with disease progression and aggressiveness. Genetic and pharmacological inhibition of RIPK2 significantly suppressed prostate cancer progression in vitro and metastasis in vivo. Multi-level proteomic analysis revealed that RIPK2 strongly regulates c-Myc protein stability and activity, largely by activating the MKK7/JNK/c-Myc phosphorylation pathway—a novel, non-canonical RIPK2 signaling pathway. Targeting RIPK2 inhibits this phosphorylation pathway, and thus promotes the degradation of c-Myc—a potent oncoprotein for which no drugs have been approved for clinical use yet. These results support targeting RIPK2 for personalized therapy in prostate cancer patients towards improving survival.

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