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dc.contributor.authorAnnabi, Borhane
dc.contributor.authorBouzeghrane, Mounia
dc.contributor.authorCurrie, Jean-Christophe
dc.contributor.authorHawkins, Robert E
dc.contributor.authorDulude, Hélène
dc.contributor.authorDaigneault, Luc
dc.contributor.authorRuiz, Marcia
dc.contributor.authorWisniewski, Jan
dc.contributor.authorGarde, Seema
dc.contributor.authorRabbani, Shafaat A
dc.contributor.authorPanchal, Chandra
dc.contributor.authorWu, Jinzi J
dc.contributor.authorBéliveau, Richard
dc.date.accessioned2009-08-04T17:13:26Z
dc.date.available2009-08-04T17:13:26Z
dc.date.issued2005
dc.identifier.citationA PSP94-derived peptide PCK3145 inhibits MMP-9 secretion and triggers CD44 cell surface shedding: implication in tumor metastasis. 2005, 22 (5):429-39 Clin. Exp. Metastasisen
dc.identifier.issn0262-0898
dc.identifier.pmid16283486
dc.identifier.doi10.1007/s10585-005-2669-1
dc.identifier.urihttp://hdl.handle.net/10541/76275
dc.description.abstractPURPOSE: PCK3145 is a synthetic peptide corresponding to amino acids 31-45 of prostate secretory protein 94, which can reduce experimental skeletal metastases and prostate tumor growth in vivo. Part of its biological action involves the reduction of circulating plasma matrix metalloproteinase (MMP)-9, a crucial mediator in extracellular matrix (ECM) degradation during tumor metastasis and cancer cell invasion. The antimetastatic mechanism of action of PCK3145 is however, not understood. EXPERIMENTAL DESIGN: HT-1080 fibrosarcoma cells were treated with PCK3145, and cell lysates used for immunoblot analysis of small GTPase RhoA and membrane type (MT)1-MMP protein expression. Conditioned media was used to monitor soluble MMP-9 gelatinolytic activity by zymography and protein expression by immunoblotting. RT-PCR was used to assess RhoA, MT1-MMP, MMP-9, RECK, and CD44 gene expression. Flow cytometry was used to monitor cell surface expression of CD44 and of membrane-bound MMP-9. Cell adhesion was performed on different purified ECM proteins, while cell migration was specifically performed on hyaluronic acid (HA). RESULTS: We found that PCK3145 inhibited HT-1080 cell adhesion onto HA, laminin-1, and type-I collagen suggesting the common implication of the cell surface receptor CD44. In fact, PCK3145 triggered the shedding of CD44 from the cell surface into the conditioned media. PCK3145 also inhibited MMP-9 secretion and binding to the cell surface. This effect was correlated to increased RhoA and MT1-MMP gene and protein expression. CONCLUSIONS: Our data suggest that PCK3145 may antagonize tumor cell metastatic processes by inhibiting both MMP-9 secretion and its potential binding to its cell surface docking receptor CD44. Such mechanism may involve RhoA signaling and increase in MT1-MMP-mediated CD44 shedding. Together with its beneficial effects in clinical trials, this is the first demonstration of PCK3145 acting as a MMP secretion inhibitor.
dc.language.isoenen
dc.subjectTumour Cellsen
dc.subjectTumour Metastasisen
dc.subject.meshAntigens, CD44
dc.subject.meshFibrosarcoma
dc.subject.meshFlow Cytometry
dc.subject.meshGene Expression Profiling
dc.subject.meshHumans
dc.subject.meshMatrix Metalloproteinase 9
dc.subject.meshNeoplasm Metastasis
dc.subject.meshPeptide Fragments
dc.subject.meshPolyesters
dc.subject.meshProstatic Secretory Proteins
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction
dc.subject.meshTumor Cells, Cultured
dc.titleA PSP94-derived peptide PCK3145 inhibits MMP-9 secretion and triggers CD44 cell surface shedding: implication in tumor metastasis.en
dc.typeArticleen
dc.contributor.departmentLaboratoire d'Oncologie Moléculaire, Département de Chimie-Biochimie, Université du Québec à Montréal, Montreal, Quebec, Canada.en
dc.identifier.journalClinical & Experimental Metastasisen
html.description.abstractPURPOSE: PCK3145 is a synthetic peptide corresponding to amino acids 31-45 of prostate secretory protein 94, which can reduce experimental skeletal metastases and prostate tumor growth in vivo. Part of its biological action involves the reduction of circulating plasma matrix metalloproteinase (MMP)-9, a crucial mediator in extracellular matrix (ECM) degradation during tumor metastasis and cancer cell invasion. The antimetastatic mechanism of action of PCK3145 is however, not understood. EXPERIMENTAL DESIGN: HT-1080 fibrosarcoma cells were treated with PCK3145, and cell lysates used for immunoblot analysis of small GTPase RhoA and membrane type (MT)1-MMP protein expression. Conditioned media was used to monitor soluble MMP-9 gelatinolytic activity by zymography and protein expression by immunoblotting. RT-PCR was used to assess RhoA, MT1-MMP, MMP-9, RECK, and CD44 gene expression. Flow cytometry was used to monitor cell surface expression of CD44 and of membrane-bound MMP-9. Cell adhesion was performed on different purified ECM proteins, while cell migration was specifically performed on hyaluronic acid (HA). RESULTS: We found that PCK3145 inhibited HT-1080 cell adhesion onto HA, laminin-1, and type-I collagen suggesting the common implication of the cell surface receptor CD44. In fact, PCK3145 triggered the shedding of CD44 from the cell surface into the conditioned media. PCK3145 also inhibited MMP-9 secretion and binding to the cell surface. This effect was correlated to increased RhoA and MT1-MMP gene and protein expression. CONCLUSIONS: Our data suggest that PCK3145 may antagonize tumor cell metastatic processes by inhibiting both MMP-9 secretion and its potential binding to its cell surface docking receptor CD44. Such mechanism may involve RhoA signaling and increase in MT1-MMP-mediated CD44 shedding. Together with its beneficial effects in clinical trials, this is the first demonstration of PCK3145 acting as a MMP secretion inhibitor.


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