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Research Article Free access | 10.1172/JCI117462

Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and modulation of sensitivity by cytokines.

M Weller, K Frei, P Groscurth, P H Krammer, Y Yonekawa, and A Fontana

Department of Internal Medicine, University of Zürich, School of Medicine, Switzerland.

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Department of Internal Medicine, University of Zürich, School of Medicine, Switzerland.

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Department of Internal Medicine, University of Zürich, School of Medicine, Switzerland.

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Department of Internal Medicine, University of Zürich, School of Medicine, Switzerland.

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Department of Internal Medicine, University of Zürich, School of Medicine, Switzerland.

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Department of Internal Medicine, University of Zürich, School of Medicine, Switzerland.

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Published September 1, 1994 - More info

Published in Volume 94, Issue 3 on September 1, 1994
J Clin Invest. 1994;94(3):954–964. https://doi.org/10.1172/JCI117462.
© 1994 The American Society for Clinical Investigation
Published September 1, 1994 - Version history
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Abstract

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.

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