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 malign ant glioma and other types of cancer. Subtilisin-like proprotein convertase s such as furin are thought to mediate TGF-beta processing. Here we report that human malignant glioma cell lines express furin mRNA and protein, exhi bit furin-like protease (FLP) activity, and release active furin into the c ell culture supernatant. FLP activity is not modulated by exogenous TGF-bet a or neutralizing TGF-beta Abs. Exposure of LN-18 and T98G glioma cell line s to the furin inhibitor, decanoyl-Arg-Val-Lys-Arg-chloromethylketone, inhi bits processing of the TGF-beta1 and TGF-beta2 precursor molecules and, con sequently, the release of mature bioactive TGF-beta molecules. Ectopic expr ession of PDX, a synthetic antitrypsin analog with antifurin activity, in t he glioma cells inhibits FLP activity, TGF-beta processing, and TGF-beta re lease. Thus, subtilisin-like proprotein convertases may represent a novel t arget for the immunotherapy of malignant glioma and other cancers or pathol ogical conditions characterized by enhanced TGF-beta bioactivity.