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PMID: 7539458 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Protooncogene bcl-2 gene transfer abrogates Fas/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic irradiation.

The Journal of clinical investigation ·Vol. 95 ·No. 6 ·1995-06-00 ·Pages 2633-43

Weller M, Malipiero U, Aguzzi A, Reed JC, Fontana A

Abstract

The majority of human malignant glioma cells express Fas/APO-1 and are susceptible to Fas/APO-1 antibody-mediated apoptosis in vitro. The sensitivity of Fas/APO-1-positive glioma cell lines to Fas/APO-1 antibody-mediated killing correlates inversely with the constitutive expression of the antiapoptotic protooncogene bcl-2. Here we report that BCL-2 protein expression of human glial tumors in vivo correlates with malignant transformation in that BCL-2 immunoreactive glioma cells were more abundant in WHO grade III/IV gliomas than in grade I/II gliomas. Fas/APO-1 antibody-sensitive human glioma cell lines stably transfected with a murine bcl-2 cDNA acquired resistance to Fas/APO-1 antibody-mediated apoptosis. Forced expression of bcl-2 also attenuated TNF alpha-mediated cytotoxicity of glioma cell lines in the presence of actinomycin D and cycloheximide and conferred partial protection from irradiation and the cancer chemotherapy drugs, cisplatin and BCNU. Preexposure of the glioma cell lines to the cytokines, IFN gamma and TNF alpha, which sensitize for Fas/APO-1-dependent killing, partially overcame bcl-2-mediated rescue from apoptosis, suggesting that multimodality immunotherapy involving cytokines and Fas/APO-1 targeting might eventually provide a promising approach to the treatment of human malignant gliomas.

Related Genes
bcl-2
MeSH Terms
Animals Antigens, Surface/physiology Apoptosis Cytokines/pharmacology DNA Damage DNA, Neoplasm/chemistry Dexamethasone/pharmacology Drug Resistance Gene Expression Regulation, Neoplastic Gene Transfer Techniques Glioma/drug therapy,pathology,radiotherapy Humans In Vitro Techniques Mice Proto-Oncogene Proteins/genetics Proto-Oncogene Proteins c-bcl-2 Proto-Oncogenes RNA, Messenger/genetics Transfection Tumor Cells, Cultured Tumor Necrosis Factor-alpha/pharmacology fas Receptor
Chemicals
Antigens, Surface Cytokines DNA, Neoplasm Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 RNA, Messenger Tumor Necrosis Factor-alpha fas Receptor Dexamethasone
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Weller M
Department of Internal Medicine, University Hospital Zürich, Switzerland.
Malipiero U
Aguzzi A
Reed J C
Fontana A
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60 references, click to expand
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI117965
Published
1995-06-00
Pages
2633-43
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC295946
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI117965 PMC Full Text View journal details
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