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 antiapoptot ic proteins that are thought to inhibit cell death via direct inhibition of caspases, Here, we report that human malignant glioma cell lines express X IAP, HIAP-1 and HIAP-2 mRNA and proteins. NAIP was not expressed, IAP prote ins were not cleaved during CD95 ligand (CD95L)-induced apoptosis, and loss of IAP protein expression was not responsible for the potentiation of CD95 L-induced apoptosis when protein synthesis was inhibited, LN-18 cells are h ighly sensitive to CD95-mediated apoptosis, whereas LN-229 cells require co -exposure to CD95L and a protein synthesis inhibitor, CHX, to acquire sensi tivity 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 ca spase 8 processing in LN-229 cells in the presence of CHX. There was consid erable overlap of the effects of XIAP on caspase processing with those of B CL-2 and the viral caspase inhibitor crm-A, These data define complex regul atory mechanisms for CD95-mediated apoptosis in glioma cells and indicate t hat there may be a distinct pathway of death receptor-mediated apoptosis th at is readily activated when protein synthesis is inhibited, The constituti ve expression of natural caspase inhibitors may play a role in the resistan ce of these cells to apoptotic stimuli that directly target caspases, inclu ding radiochemotherapy and immune-mediated tumor cell lysis.