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

被引:22
作者
Annabi, Borhane
Bouzeghrane, Mounia
Currie, Jean-Christophe
Dulude, Helene
Daigneault, Luc
Garde, Seema
Rabbani, Shafaat A.
Panchal, Chandra
Wu, Jinzi J.
Beliveau, Richard
机构
[1] Univ Quebec, Ctr Biomed, Dept Chim, Mol Oncol Lab, Montreal, PQ, Canada
[2] UQAM, Hop St Justine, Ctr Cancerol Charles Bruneau, Montreal, PQ, Canada
[3] Procyon BioPharma Inc, Montreal, PQ, Canada
[4] McGill Univ, Ctr Hlth, Dept Med Physiol & Oncol, Montreal, PQ, Canada
关键词
extracellular signal-regulated protein kinase; laminin receptor; prostate cancer; metastasis; HuR; metalloproteinase-9;
D O I
10.1097/01.cad.0000203388.68034.06
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:429 / 438
页数:10
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