Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and modulation of sensitivity by cytokines.
Fas/APO-1 is a transmembrane protein of the nerve growth factor/TNF alpha receptor family which signals apoptotic cell death in susceptible target cells. We have investigated the susceptibility of seven human malignant glioma cell lines to Fas/APO-1-dependent apoptosis. Sensitivity to Fas/APO-1 antibody-mediated cell killing correlated with cell surface expression of Fas/APO-1. Expression of Fas/APO-1 as well as Fas/APO-1-dependent cytotoxicity were augmented by preexposure of human malignant glioma cells to IFN gamma and TNF alpha. Further, pretreatment with TGF beta 2, IL1 and IL8 enhanced Fas/APO-1 antibody-induced glioma cell apoptosis whereas other cytokines including TNF beta, IL6, macrophage colony-stimulating factor, IL10 and IL13 had no such effect. None of the human malignant glioma cell lines was susceptible to TNF alpha-induced cytotoxicity. Fas/APO-1 antibody-sensitive glioma cell lines (n = 5), but not Fas/APO-1 antibody-resistant glioma cell lines (n = 2), became sensitive to TNF alpha when co-treated with inhibitors of RNA and protein synthesis. Resistance of human glioma cells to Fas/APO-1 antibody-mediated apoptosis was mainly related to low level expression of Fas/APO-1 and appeared not to be linked to overexpression of the anti-apoptotic protooncogene, bcl-2. Given the resistance of human malignant glioma to surgery, irradiation, chemotherapy and immunotherapy, we propose that Fas/APO-1 may be a promising target for a novel locoregionary approach to human malignant glioma. This strategy gains support from the demonstration of Fas/APO-1 expression in ex vivo human malignant glioma specimens and from the absence of Fas/APO-1 in normal human brain parenchyma.
Weller
M
M
Department of Internal Medicine, University of Zürich, School of Medicine, Switzerland.
Frei
K
K
Groscurth
P
P
Krammer
P H
PH
Yonekawa
Y
Y
Fontana
A
A
D000906:Antibodies / Q000494:pharmacology*; D000954:Antigens, Surface / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000032:analysis; D005434:Flow Cytometry; D005910:Glioma / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008854:Microscopy, Electron; D011956:Receptors, Cell Surface / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity; D019014:fas Receptor
D000906:Antibodies; D000954:Antigens, Surface; D016207:Cytokines; D004273:DNA, Neoplasm; D007378:Interleukins; D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma