Abstract
Studies on interaction of tumor cells with ECM components showed increased extracellular protease activity mediated by the family of matrix metalloproteinases (MMPs). Here we studied the effect of human prostate adenocarcinoma PC-3 cells-fibronectin (FN) interaction on MMPs and the underlying signaling pathways. Culturing of PC-3 cells on FN-coated surface upregulated MMP-9 and MMP-1. This response is abrogated by the blockade of α5 integrin. siRNA and inhibitor studies indicate possible involvement of phosphatidyl-inositol-3-kinase (PI-3K), focal adhesion kinase (FAK) and nuclear factor-kappaB (NF-κB) in FN-induced upregulation of MMPs. FN treatment also enhanced phosphorylation of FAK, PI3K, protein kinase B (PKB or Akt), nuclear translocation of NF-κB, surface expression of CD-44, and cell migration. Our findings indicate that, binding of PC-3 cells to FN, possibly via α5β1 integrin, induces signaling involving FAK, PI-3K, Akt, NF-κB followed by upregulation of MMP-9 and MMP-1. CD-44 may have role in modulating MMP-9 activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Cadherins / metabolism
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Cell Line, Tumor
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Cell Movement / drug effects
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Fibronectins / pharmacology*
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Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors
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Focal Adhesion Protein-Tyrosine Kinases / genetics
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Focal Adhesion Protein-Tyrosine Kinases / metabolism
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Humans
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Hyaluronan Receptors / metabolism
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Integrin alpha5beta1 / metabolism
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Male
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Matrix Metalloproteinase 1 / genetics
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Matrix Metalloproteinase 1 / metabolism*
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism*
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NF-kappa B / metabolism
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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RNA, Messenger / metabolism
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RNA, Small Interfering
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Signal Transduction
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Up-Regulation / drug effects
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Cadherins
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Fibronectins
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Hyaluronan Receptors
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Integrin alpha5beta1
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NF-kappa B
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Phosphoinositide-3 Kinase Inhibitors
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RNA, Messenger
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RNA, Small Interfering
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Vascular Endothelial Growth Factor A
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integrin-linked kinase
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Focal Adhesion Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Matrix Metalloproteinase 9
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Matrix Metalloproteinase 1