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-beta2 (TGF-beta2). We here report that BCL-2-expressing cells show enhanced expression and activity of the proprotein convertase, furin, which processes metalloproteinases (MMP) and TGF-beta. 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-beta or hepatocyte growth factor (HGF). A neutralizing TGF-beta 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-beta2. Consequently, HGF and BCL-2 family proteins use a furin-dependent pathway to promote invasion via TGF-beta and MMP in human malignant glioma cells and the pro-invasive properties of TGF-beta require furin- dependent MMP activity.
Wick
Wolfgang
W
Laboratory of Molecular Neuro-Oncology, Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Medical School, Tübingen, Germany. wolfgang.wick@uni-tuebingen.de
Wild-Bode
Christine
C
Frank
Brigitte
B
Weller
Michael
M
D045744:Cell Line, Tumor; D045683:Furin / Q000235:genetics / Q000378:metabolism*; D005910:Glioma / Q000378:metabolism* / Q000473:pathology*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010447:Peptide Hydrolases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor; D010447:Peptide Hydrolases; D045683:Furin; D020782:Matrix Metalloproteinases