Expression and biological activity of X-linked inhibitor of apoptosis (XIAP) in human malignant glioma.
The inhibitor-of-apoptosis (IAP) proteins are a novel family of antiapoptotic proteins that are thought to inhibit cell death via direct inhibition of caspases. Here, we report that human malignant glioma cell lines express XIAP, HIAP-1 and HIAP-2 mRNA and proteins. NAIP was not expressed. IAP proteins were not cleaved during CD95 ligand (CD95L)-induced apoptosis, and loss of IAP protein expression was not responsible for the potentiation of CD95L-induced apoptosis when protein synthesis was inhibited. LN-18 cells are highly sensitive to CD95-mediated apoptosis, whereas LN-229 cells require co-exposure to CD95L and a protein synthesis inhibitor, CHX, to acquire sensitivity to apoptosis. Adenoviral XIAP gene transfer blocked caspase 8 and 3 processing in both cell lines in the absence of CHX. Apoptosis was blocked in the absence and in the presence of CHX. However, XIAP failed to block caspase 8 processing in LN-229 cells in the presence of CHX. There was considerable overlap of the effects of XIAP on caspase processing with those of BCL-2 and the viral caspase inhibitor crm-A. These data define complex regulatory mechanisms for CD95-mediated apoptosis in glioma cells and indicate that there may be a distinct pathway of death receptor-mediated apoptosis that is readily activated when protein synthesis is inhibited. The constitutive expression of natural caspase inhibitors may play a role in the resistance of these cells to apoptotic stimuli that directly target caspases, including radiochemotherapy and immune-mediated tumor cell lysis.
Wagenknecht
B
B
Laboratory of Molecular Neuro-Oncology, Hoppe-Seyler-Strasse 3, Germany.
Glaser
T
T
Naumann
U
U
Kügler
S
S
Isenmann
S
S
Bähr
M
M
Korneluk
R
R
Liston
P
P
Weller
M
M
D000256:Adenoviridae / Q000235:genetics; D016375:Antisense Elements (Genetics); D017209:Apoptosis / Q000235:genetics*; D001932:Brain Neoplasms; D020169:Caspases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D005910:Glioma; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics; D011506:Proteins / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D051636:X-Linked Inhibitor of Apoptosis Protein; D019014:fas Receptor / Q000235:genetics
D016375:Antisense Elements (Genetics); D009363:Neoplasm Proteins; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D019014:fas Receptor; D020169:Caspases