BCL‐2‐induced glioma cell invasiveness depends on furin‐like proteases

Migration and invasion are prerequisites for the neoplastic phenotype of malignant glioma. Ectopic expression of BCL‐2 enhances migration and invasion of glioma cells and promotes their synthesis of transforming growth factor‐β2 (TGF‐β2). We here report that BCL‐2‐expressing cells show enhanced expression and activity of the proprotein convertase, furin, which processes metalloproteinases (MMP) and TGF‐β. Consistent with a biological role for a BCL‐2‐dependent increase in furin‐like protease (FLP) activity, BCL‐2‐expressing cells exhibit enhanced MMP activity. Both a pseudosubstrate furin inhibitor, decanoyl‐Arg‐Val‐Lys‐Arg‐chloromethylketone (dec‐RVKR‐cmk), or alpha 1‐anti‐trypsin Portland (PDX), a recombinant furin‐inhibitory protein, suppress constitutive and BCL‐2‐mediated MMP activity and invasion. This inhibition is not overcome by TGF‐β or hepatocyte growth factor (HGF). A neutralizing TGF‐β antibody attenuates, but not abrogates, the invasive properties conferred by exogenous expression of BCL‐2, whereas the MMP inhibitor o‐phenantroline (o‐PA) abolishes the pro‐invasive action of BCL‐2. Exogenous HGF results in enhanced, and expression of dominant‐negative ezrin in reduced, FLP activity, and dec‐RVKR‐cmk blunts the HGF‐induced expression of mature TGF‐β2. Consequently, HGF and BCL‐2 family proteins use a furin‐dependent pathway to promote invasion via TGF‐β and MMP in human malignant glioma cells and the pro‐invasive properties of TGF‐β require furin‐ dependent MMP activity.