Protease Inhibitors Prevent Plasminogen-Mediated, But Not Pemphigus Vulgaris-Induced, Acantholysis in Human Epidermis

Schuh, Theda; Besch, Robert; Braungart, Evelyn; Flaig, Michael J.; Douwes, Kathrin; Sander, Christian; Magdolen, Viktor; Probst, Christopher; Wosikowski, Katja; Degitz, Klaus

doi:10.1515/bc.2003.035

Cited by 13 publications

(15 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These proteins are overexpressed in variety of malignancies, including breast, ovarian, glioma, and prostate cancers, and have been demonstrated to be essential in the maintenance of invasive and metastatic phenotypes (16). Several studies using in vitro and in vivo animal models have shown that either neutralizing uPA and/or uPAR function or blocking expression of these molecules significantly inhibits tumor invasion and metastasis in many cancers (5,(33)(34)(35)(36). Although both uPA and uPAR are widely implicated in prostate tumor progression, the extent of their interaction in relation to the tumorigenicity of prostate cancer is not well understood.…”

Section: Discussionmentioning

confidence: 99%

“…This has proven particularly true for human prostate cancer cells, which form primary tumors and metastases with much lower efficiency when implanted ectopically in nude mice. Given that uPA and uPAR are frequently overexpressed in many cancers, uPA is considered a very important target molecule for cancer therapy (16,33,34). Recently, in vivo therapies that target uPA or uPAR in various cancers have been reported by several research groups (5,37,38).…”

Section: Discussionmentioning

confidence: 99%

“…UPA-or uPAR-neutralizing antibodies (33), protease inhibitors (34), urokinase-specific inhibitors (5,35,36), uPA or uPAR antisense oligonucleotides (11,16,37,38), and small molecules that target uPA or uPAR (39 40) are being investigated as possible strategies to block either uPA or uPAR activity, thereby causing the suppression of tumor growth, invasion, and metastasis.…”

mentioning

confidence: 99%

See 2 more Smart Citations

RNA Interference-directed Knockdown of Urokinase Plasminogen Activator and Urokinase Plasminogen Activator Receptor Inhibits Prostate Cancer Cell Invasion, Survival, and Tumorigenicity in Vivo

Pulukuri

Gondi

Lakka

et al. 2005

Journal of Biological Chemistry

245

View full text Add to dashboard Cite

The invasive ability of tumor cells plays a key role in prostate cancer metastasis and is a major cause of treatment failure. Urokinase plasminogen activator-(uPA) and its receptor (uPAR)-mediated signaling have been implicated in tumor cell invasion, survival, and metastasis in a variety of cancers. This study was undertaken to investigate the biological roles of uPA and uPAR in prostate cancer cell invasion and survival, and the potential of uPA and uPAR as targets for prostate cancer therapy. uPA and uPAR expression correlates with the metastatic potential of prostate cancer cells. Thus, therapies designed to inhibit uPA and uPAR expression would be beneficial. LNCaP, DU145, and PC3 are prostate cancer cell lines with low, moderate, and high metastatic potential, respectively, as demonstrated by their capacity to invade the extracellular matrix. In this study we utilized small hairpin RNAs (shRNAs), also referred to as small interfering RNAs, to target human uPA and uPAR. These small interfering RNA constructs significantly inhibited uPA and uPAR expression at both the mRNA and protein levels in the highly metastatic prostate cancer cell line PC3. Our data demonstrated that uPA-uPAR knockdown in PC3 cells resulted in a dramatic reduction of tumor cell invasion as indicated by a Matrigel invasion assay. Furthermore, simultaneous silencing of the genes for uPA and uPAR using a single plasmid construct expressing shRNAs for both uPA and uPAR significantly reduced cell viability and ultimately resulted in the induction of apoptotic cell death. RNA interference for uPA and uPAR also abrogated uPA-uPAR signaling to downstream target molecules such as ERK1/2 and Stat 3. In addition, our results demonstrated that intratumoral injection with the plasmid construct expressing shRNAs for uPA and uPAR almost completely inhibited established tumor growth and survival in an orthotopic mouse prostate cancer model. These findings uncovered evidence of a complex signaling network operating downstream of uPA-uPAR that actively advances tumor cell invasion, proliferation, and survival of prostate cancer cells. Thus, RNA interference-directed targeting of uPA and uPAR is a convenient and novel tool for studying the biological role of the uPA-uPAR system and raises the potential of its application for prostate cancer therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

RNA Interference-directed Knockdown of Urokinase Plasminogen Activator and Urokinase Plasminogen Activator Receptor Inhibits Prostate Cancer Cell Invasion, Survival, and Tumorigenicity in Vivo

Pulukuri

Gondi

Lakka

et al. 2005

Journal of Biological Chemistry

245

View full text Add to dashboard Cite

show abstract

“…Schuh et al . [29] tested inhibitors of the plasminogen activator system (anti-uPA, anti-tPA, anti-plasmin) with regard to their potential protective role. The authors found that these inhibitors failed to prevent PV-IgG mediated acantholysis, but acantholysis was effectively inhibited by the synthetic active site serine protease inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic activity of circulating anti-desmoglein-3 autoantibodies isolated from pemphigus vulgaris patients

Boncela¹,

Smolarczyk²,

Kowaléwski³

et al. 2012

aoms

View full text Add to dashboard Cite

IntroductionThere are scarce data on immunochemical properties of pemphigus antibodies detected in clinical remission in pemphigus vulgaris (PV) patients. The aim of the study was to compare biological activity of anti-Dsg3 autoantibodies purified from the sera of PV patients in active stage and in clinical remission.Material and methodsThe effect of purified antibodies on expression of procaspase-3, Bax, Bcl-2, uPAR, IL-1β, IL-6, and TNF-α mRNAs in the HaCaT keratinocytes was evaluated by Western blot and RT-PCR method.ResultsIncubation of HaCaT cells with anti-Dsg-3 autoantibodies caused their binding to cell membranes surfaces. Anti-Dsg3 autoantibodies isolated from the patients in active stage and clinical remission showed proapoptotic effect, caused enhanced expression of analyzed proinflammatory cytokines’ mRNAs and uPAR mRNA.ConclusionsOur data revealed similar pathogenic activity of anti Dsg-3 autoantibodies isolated from active and clinical remission PV patients.

show abstract

“…The human organ culture model has been very valuable in obtaining information on the mechanisms of acantholysis and, moreover, has also been used to test old and new therapeutic drugs for pemphigus, for example, hydrocortisone [13], dapsone [13], methylprednisolone [17], and protease inhibitors [15]. Although most popular in the eighties, it is still used today, often in combination with other models [16, 25–28].…”

Section: Organ Cultures Of Human Skinmentioning

confidence: 99%

Experimental Human Cell and Tissue Models of Pemphigus

Wier

Pas

Jonkman

2010

Dermatology Research and Practice

View full text Add to dashboard Cite

Pemphigus is a chronic mucocutaneous autoimmune bullous disease that is characterized by loss of cell-cell contact in skin and/or mucous membranes. Past research has successfully identified desmosomes as immunological targets and has demonstrated that acantholysis is initiated through direct binding of IgG. The exact mechanisms of acantholysis, however, are still missing. Experimental model systems have contributed considerably to today's knowledge and are still a favourite tool of research. In this paper we will describe to what extent human cell and tissue models represent the in vivo situation, for example, organ cultures of human skin, keratinocyte cultures, and human skin grafted on mice and, furthermore, how suitable they are to study the pathogenesis of pemphigus. Organ cultures closely mimic the architecture of the epidermis but are less suitable to answer posed biochemical questions. Cultured keratinocyte monolayers are convenient in this respect, but their desmosomal make-up in terms of adhesion molecules does not exactly reflect the in vivo situation. Reconstituted skin is a relatively new model that approaches organ culture. In models of human skin grafted on mice, acantholysis can be studied in actual human skin but now with all the advantages of an animal model.

show abstract

Protease Inhibitors Prevent Plasminogen-Mediated, But Not Pemphigus Vulgaris-Induced, Acantholysis in Human Epidermis

Cited by 13 publications

References 23 publications

RNA Interference-directed Knockdown of Urokinase Plasminogen Activator and Urokinase Plasminogen Activator Receptor Inhibits Prostate Cancer Cell Invasion, Survival, and Tumorigenicity in Vivo

RNA Interference-directed Knockdown of Urokinase Plasminogen Activator and Urokinase Plasminogen Activator Receptor Inhibits Prostate Cancer Cell Invasion, Survival, and Tumorigenicity in Vivo

Pathogenic activity of circulating anti-desmoglein-3 autoantibodies isolated from pemphigus vulgaris patients

Experimental Human Cell and Tissue Models of Pemphigus

Contact Info

Product

Resources

About