Caspase-1 mediates Fas-induced apoptosis and is up-regulated by interferon-gamma in human astrocytoma cells.
Resistance to Fas-mediated apoptosis contributes to tumor evasion from the host immune system and enables tumors to mediate alternative responses such as inflammation and angiogenesis. In this study, we investigated the molecular mechanisms of the resistance to Fas-mediated apoptosis and sensitization to Fas-induced cell death by IFN-gamma in human astrocytoma cells. To address this, we investigated the expression of thirty-three genes related to the Fas signal transduction pathways using RNase protection assay in five different human astrocytoma cells. Patterns of expression of these genes were similar between different cell lines and did not correlate with sensitivity to Fas-mediated cell death. Treatment with IFN-gamma increased the mRNA expression of caspases-1, -4 and -7 in addition to those of Fas and TRAIL in a time- and dose-dependent manner. Studies using specific caspase inhibitors showed that Fas-induced cell death was mediated by caspases-1, -3 and 8 in the Fas-sensitive human astrocytoma cell lines, CRT-J and U87-MG. We further demonstrated that these caspases were proteolytically cleaved upon Fas ligation in these cells. Interestingly, caspase-1 protein expression but not that of caspase-3 nor -8 was up-regulated by IFN-gamma only in Fas-sensitive CRT-J cells but not in Fas-resistant U373-MG cells. These results collectively suggest that caspase-1, along with caspases-3 and -8, mediate Fas-induced cell death in human astrocytoma cells, and post-transcriptional regulation of caspase-1 may determine the responsiveness to IFN-gamma-induced sensitization to Fas-mediated apoptosis.
Choi
Chulhee
C
Division of Molecular Life Sciences and Center for Cell Signaling Research, Ewha Womans University, Seoul, Korea. cchoi@ewha.ac.kr
Jeong
Eunjoo
E
Benveniste
Etty N
EN
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001254:Astrocytoma / Q000378:metabolism*; D015153:Blotting, Western; D020170:Caspase 1 / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation; D019014:fas Receptor / Q000187:drug effects / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007371:Interferon-gamma; D020170:Caspase 1