Abstract
TGF-beta is a putative mediator of immunosuppression associated with malignant glioma and other types of cancer. Subtilisin-like proprotein convertases such as furin are thought to mediate TGF-beta processing. Here we report that human malignant glioma cell lines express furin mRNA and protein, exhibit furin-like protease (FLP) activity, and release active furin into the cell culture supernatant. FLP activity is not modulated by exogenous TGF-beta or neutralizing TGF-beta Abs. Exposure of LN-18 and T98G glioma cell lines to the furin inhibitor, decanoyl-Arg-Val-Lys-Arg-chloromethylketone, inhibits processing of the TGF-beta1 and TGF-beta2 precursor molecules and, consequently, the release of mature bioactive TGF-beta molecules. Ectopic expression of PDX, a synthetic antitrypsin analog with antifurin activity, in the glioma cells inhibits FLP activity, TGF-beta processing, and TGF-beta release. Thus, subtilisin-like proprotein convertases may represent a novel target for the immunotherapy of malignant glioma and other cancers or pathological conditions characterized by enhanced TGF-beta bioactivity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Transformed
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Cytoplasm / enzymology*
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Cytoplasm / physiology
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Enzyme Activation / genetics
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Enzyme Activation / immunology
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Furin
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Glioblastoma / enzymology*
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Glioblastoma / genetics
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Glioblastoma / metabolism
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Humans
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Immunosuppressive Agents / antagonists & inhibitors
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Immunosuppressive Agents / metabolism*
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Protein Precursors / antagonists & inhibitors
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Protein Precursors / biosynthesis
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Protein Precursors / metabolism*
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Protein Processing, Post-Translational / immunology*
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Subtilisins / antagonists & inhibitors
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Subtilisins / biosynthesis
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Subtilisins / metabolism*
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Transfection
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / biosynthesis
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Transforming Growth Factor beta / metabolism*
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Transforming Growth Factor beta2
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Tumor Cells, Cultured
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alpha 1-Antitrypsin / genetics
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alpha 1-Antitrypsin / physiology
Substances
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Immunosuppressive Agents
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Protein Precursors
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TGFB2 protein, human
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Transforming Growth Factor beta
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Transforming Growth Factor beta2
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alpha 1-Antitrypsin
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alpha 1-antitrypsin Portland
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Subtilisins
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Furin