A PSP94-derived peptide PCK3145 inhibits MMP-9 secretion and triggers CD44 cell surface shedding: implication in tumor metastasis.

2.50
Hdl Handle:
http://hdl.handle.net/10541/76275
Title:
A PSP94-derived peptide PCK3145 inhibits MMP-9 secretion and triggers CD44 cell surface shedding: implication in tumor metastasis.
Authors:
Annabi, Borhane; Bouzeghrane, Mounia; Currie, Jean-Christophe; Hawkins, Robert E; Dulude, Hélène; Daigneault, Luc; Ruiz, Marcia; Wisniewski, Jan; Garde, Seema; Rabbani, Shafaat A; Panchal, Chandra; Wu, Jinzi J; Béliveau, Richard
Abstract:
PURPOSE: 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.
Affiliation:
Laboratoire d'Oncologie Moléculaire, Département de Chimie-Biochimie, Université du Québec à Montréal, Montreal, Quebec, Canada.
Citation:
A 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. Metastasis
Journal:
Clinical & Experimental Metastasis
Issue Date:
2005
URI:
http://hdl.handle.net/10541/76275
DOI:
10.1007/s10585-005-2669-1
PubMed ID:
16283486
Type:
Article
Language:
en
ISSN:
0262-0898
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
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.en
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

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