Abstract
Dipeptidyl peptidase IV (DPPIV) is a serine protease with tumor suppressor function. It regulates the activities of mitogenic peptides implied in cancer development. Progression of benign prostate cancer to malignant metastasis is linked to increased production of basic fibroblast growth factor (bFGF), a powerful mitogen. In this study, using in vitro model system we show that DPPIV loss is associated with increased bFGF production in metastatic prostate cancer cells. DPPIV reexpression in prostate cancer cells blocks nuclear localization of bFGF, reduces bFGF levels, inhibits mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)1/2 activation, and decreases levels of urokinase-type plasminogen activator, known downstream effectors of bFGF signaling pathway. These molecular changes were accompanied by induction of apoptosis, cell cycle arrest, inhibition of in vitro cell migration, and invasion. Silencing of DPPIV by small interfering RNA resulted in increased bFGF levels and restoration of mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)1/2 activation. These results indicate that DPPIV inhibits the malignant phenotype of prostate cancer cells by blocking bFGF signaling pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Deaminase / biosynthesis
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Adenosine Deaminase / deficiency
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Adenosine Deaminase / genetics
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Adenosine Deaminase / physiology*
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Cell Growth Processes / physiology
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Cell Line, Tumor
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Cell Movement / physiology
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Cell Nucleus / enzymology
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Cell Nucleus / metabolism
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Dipeptidyl Peptidase 4 / biosynthesis
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Dipeptidyl Peptidase 4 / genetics
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Dipeptidyl Peptidase 4 / physiology*
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Enzyme Activation
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Fibroblast Growth Factor 2 / antagonists & inhibitors*
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Fibroblast Growth Factor 2 / biosynthesis
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Fibroblast Growth Factor 2 / metabolism
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Fibronectins / biosynthesis
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Glycoproteins / biosynthesis
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Glycoproteins / deficiency
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Glycoproteins / genetics
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Glycoproteins / physiology*
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Humans
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MAP Kinase Signaling System / physiology
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Male
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Neoplasm Invasiveness
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Phosphorylation
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Prostatic Neoplasms / enzymology*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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RNA, Small Interfering / genetics
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Urokinase-Type Plasminogen Activator / biosynthesis
Substances
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Fibronectins
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Glycoproteins
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RNA, Small Interfering
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Fibroblast Growth Factor 2
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Mitogen-Activated Protein Kinases
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DPP4 protein, human
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Dipeptidyl Peptidase 4
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Urokinase-Type Plasminogen Activator
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Adenosine Deaminase