Processing of immunosuppressive pro-TGF-beta 1,2 by human glioblastoma cells involves cytoplasmic and secreted furin-like proteases.
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.
Leitlein
J
J
Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, Tübingen, Germany.
Aulwurm
S
S
Waltereit
R
R
Naumann
U
U
Wagenknecht
B
B
Garten
W
W
Weller
M
M
Platten
M
M
D002461:Cell Line, Transformed; D003593:Cytoplasm / Q000201:enzymology* / Q000502:physiology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D045683:Furin; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D013381:Subtilisins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D053781:Transforming Growth Factor beta2; D014407:Tumor Cells, Cultured; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000502:physiology
D007166:Immunosuppressive Agents; D011498:Protein Precursors; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D000515:alpha 1-Antitrypsin; C113421:alpha 1-antitrypsin Portland; D013381:Subtilisins; D045683:Furin