Inhibition of MMP-9 secretion by the anti-metastatic PSP94-derived peptide PCK3145 requires cell surface laminin receptor signaling

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. These anti-metastatic and anti-tumoral effects of PCK3145 are partially explained by the in-vivo and in-vitro decrease in ma...

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Veröffentlicht in:Anti-cancer drugs 2006-04, Vol.17 (4), p.429-438
Hauptverfasser: Annabi, Borhane, Bouzeghrane, Mounia, Currie, Jean-Christophe, Dulude, Hélène, Daigneault, Luc, Garde, Seema, Rabbani, Shafaat A, Panchal, Chandra, Wu, Jinzi J, Béliveau, Richard
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Sprache:eng
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Zusammenfassung: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. These anti-metastatic and anti-tumoral effects of PCK3145 are partially explained by the in-vivo and in-vitro decrease in matrix metalloproteinase (MMP)-9 extracellular levels through as yet unidentified molecular mechanisms of action. Gelatin zymography and immunoblots were used to monitor the levels of secreted MMP-9 from HT-1080 cells. Flow cytometry was used to monitor HT-1080 cell surface binding of FITC-labeled PCK3145 and biotin-labeled laminin. PCK3145-coated cell culture dishes were used to monitor cell adhesion. HT-1080 cell lysates were used for immunoblotting of HuR, extracellular signal-regulated protein kinase (ERK) and phospho-ERK. Total RNA was isolated and RT-PCR used to monitor HuR gene expression. We found that PCK3145 bound to the HT-1080 cell surface and that this binding rapidly triggered ERK phosphorylation that, ultimately, led to a reduction of secreted MMP-9. Laminin inhibited both cell surface binding and ERK phosphorylation by PCK3145. Overexpression of the 67-kDa laminin receptor led to an increased binding of the cells to PCK3145. HuR, a protein that can bind to and stabilize MMP-9 mRNA, was found to be downregulated by PCK3145. The mitogen-activated protein kinase/ERK (MEK) inhibitor PD98059 as well as native laminin and SIKVAV laminin-derived peptide prevented that downregulation. Our data suggest that PCK3145 rapidly triggers intracellular signaling through cell surface laminin receptors. This leads to decreased HuR expression and subsequent destabilization of MMP-9 transcripts. This is the first molecular evidence demonstrating the intracellular signaling and anti-metastatic mechanism of action of PCK3145 that leads to the inhibition of MMP-9 secretion.
ISSN:0959-4973
1473-5741
DOI:10.1097/01.cad.0000203388.68034.06