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The Journal of Immunology, 2001, 166: 7238-7243.
Copyright © 2001 by The American Association of Immunologists

Processing of Immunosuppressive Pro-TGF-{beta}1,2 by Human Glioblastoma Cells Involves Cytoplasmic and Secreted Furin-Like Proteases1

Jens Leitlein*, Steffen Aulwurm*, Robert Waltereit*, Ulrike Naumann*, Bettina Wagenknecht*, Wolfgang Garten{dagger}, Michael Weller2,* and Michael Platten*

* Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, Tübingen, Germany; and {dagger} Institute of Virology, University of Marburg, Marburg, Germany

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-{beta}1 and TGF-{beta}2 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.




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