Urokinase-Type Plasminogen Activator Expression in Human Prostate Carcinomas

Veldhuizen, Peter J. Van; Sadasivan, Raj; Cherian, Rachel; Wyatt, Angel

doi:10.1016/s0002-9629(15)41739-2

Cited by 37 publications

(31 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The association of the plasminogen activation system with tumor invasion and dissemination is well documented (43,44). Hepsin also activates the latent form of the invasive growth factor HGF (17,18), and both HGF and uPA have been implicated in prostate cancer growth and metastasis (45)(46)(47)(48). Moreover, by activating pro-HGF, hepsin may directly regulate the local levels of its substrate pro-uPA since HGF was shown to induce pro-uPA transcription and protein synthesis (49,50).…”

Section: Discussionmentioning

confidence: 99%

Pro-urokinase-type Plasminogen Activator Is a Substrate for Hepsin

Moran¹,

Li²,

Fan³

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Hepsin, a type II transmembrane serine protease, is strongly up-regulated in prostate cancer. Hepsin overexpression in a mouse prostate cancer model resulted in tumor progression and metastasis, associated with basement membrane disorganization. We investigated whether hepsin enzymatic activity was linked to the basement membrane defects by examining its ability to initiate the plasminogen/plasmin proteolytic pathway. Because plasminogen is not processed by hepsin, we investigated the upstream activators, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator. Enzymatic assays with a recombinant soluble form of hepsin demonstrated that hepsin did not cleave pro-tissue-type plasminogen activator but efficiently converted pro-uPA into high molecular weight uPA by cleavage at the Lys 158 -Ile 159 (P 1 -P 1 ) peptide bond. uPA generated by hepsin displayed enzymatic activity toward small synthetic and macromolecular substrates indistinguishable from uPA produced by plasmin. The catalytic efficiency of pro-uPA activation by hepsin (k cat /K m 4.8 ؋ 10 5 M ؊1 s ؊1 ) was similar to that of plasmin, which is considered the most potent pro-uPA activator and was about 6-fold higher than that of matriptase. Conversion of pro-uPA was also demonstrated with cell surface-expressed full-length hepsin. A stable hepsinoverexpressing LnCaP cell line converted pro-uPA into high molecular weight uPA at a rate of 6.6 ؎ 1.9 nM uPA h ؊1 , which was about 3-fold higher than LnCaP cells expressing lower hepsin levels on their surface. In conclusion, the ability of hepsin to efficiently activate pro-uPA suggests that it may initiate plasmin-mediated proteolytic pathways at the tumor/stroma interface that lead to basement membrane disruption and tumor progression.Hepsin is a type II transmembrane serine protease expressed on the surface of epithelial cells. The 417-amino acid protein is composed of a short N-terminal cytoplasmic domain, a transmembrane domain, and a single scavenger receptor cysteinerich domain that packs tightly against the C-terminal protease domain (1). The physiologic function of hepsin remains unknown. Despite its expression in the very early stages of embryogenesis (2), hepsin-deficient mice were viable and developed normally (3, 4). The studies further showed that hepsin was not essential for liver regeneration and for coagulationrelated physiological functions (3, 4). However, hepsin has been implicated in ovarian cancer (5) and prostate cancer (6 -11), where several gene expression studies have identified it as one of the most highly induced genes. Hepsin RNA levels were found to be low in normal prostate and benign hyperplasia but strongly increased in prostate carcinoma, particularly in advanced stages (8 -10). Hepsin protein staining with a monoclonal anti-hepsin antibody showed that hepsin expression was highest at sites of bone metastasis and in late stage primary tumors (12), which is consistent with the finding that increased hepsin RNA levels correlated with higher Gleason grades...

show abstract

Section: Discussionmentioning

confidence: 99%

Pro-urokinase-type Plasminogen Activator Is a Substrate for Hepsin

Moran¹,

Li²,

Fan³

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The urokinase plasminogen activator (UPA) was originally isolated from human urine and is expressed in PCA specimens. 4 Prostatespecific antigen (PSA) is a kallikrein-like serine protease now widely accepted as a useful serum marker for PCA detection and monitoring. 5 Some investigators believe that PSA plays a direct role in modulating prostate cancer cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Patterns of protease production during prostate cancer progression: proteomic evidence for cascades in a transgenic model

Bok

Hansell²,

Nguyen³

et al. 2003

Prostate Cancer Prostatic Dis

View full text Add to dashboard Cite

Extracellular proteases are recognized as critical factors in the progression of a number of carcinomas, including prostate cancer. Matrix metalloproteases (MMP) are important in processes of tumor growth, invasion and dissemination, but other classes of proteases, such as serine and cysteine proteases, also contribute. We utilized the TRAMP model for prostate cancer to elucidate proteases involved in prostate cancer progression. General proteomic analysis was performed on normal murine prostate, early TRAMP tumors and advanced TRAMP tumors, as well as normal and involved lymph nodes. Zymography and antigenic analyses revealed increased expression of mainly pro-MMP in early TRAMP tumors but substantial elaboration of activated MMP only in late TRAMP tumors. Progressive increase in cysteine, serine and certain membrane-bound proteases from normal to early to advanced prostate tumors, was also seen. Our results implicate pericellular proteases as initiators of major proteolytic cascades during tumor progression and suggest targets for maximal therapeutic effect.

show abstract

“…22,23 By IHC, u-PA expression has been found to be increased in cancer specimens with extracapsular extension vs specimens without extracapsular extension. 24 Endothelial cells also secrete u-PA, and this facilitates their ability to degrade tumor matrix and establish neovascularization. 25 Expression of a mutant, proteolytically inactive form of u-PA is shown to signi®cantly decrease CaP tumor growth and angiogenesis in vivo.…”

Section: Introductionmentioning

confidence: 99%