Ectopic and IFN-induced expression of Fas overcomes resistance to Fas-mediated apoptosis in multiple myeloma cells.
Multiple myeloma (MM) is an as-yet incurable B-cell malignancy. Increased survival in vitro is a hallmark of MM cells, implying that a therapeutic potential may lie in circumventing antiapoptotic signals. We have previously reported that interferons (IFNs) sensitize MM cells to Fas/CD95-mediated apoptosis. In the present study, we explore the mechanism underlying this effect. In a wide screening of apoptosis-related genes, Apo2L/TRAIL (tumor necrosis factor [TNF]-related apoptosis inducing ligand) and Fas were identified as IFN targets. Sensitization to Fas-mediated apoptosis by IFNs was not affected by blocking Apo2L/TRAIL, suggesting that Apo2L/TRAIL is not a key mediator in this process. In contrast, we found that an elevated Fas expression was functionally linked to increased susceptibility to Fas-mediated apoptosis. This was further supported by the finding that IFN treatment enhanced Fas-mediated caspase-8 activation, one of the earliest signaling events downstream receptor activation. In addition, IFN treatment attenuated the interleukin 6 (IL-6)-dependent activation of signal transducer and activator of transcription 3 (Stat3), interfering with a known survival pathway in MM that has previously been linked with resistance to Fas-mediated apoptosis. Taken together, our results show that IFN-induced up-regulation of Fas sensitizes MM cells to Fas-mediated apoptosis and suggest that attenuation of Stat3 activation may be a potentially important event in this process.
Dimberg
Lina Y
LY
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Dimberg
Anna I
AI
Ivarsson
Karolina
K
Strömberg
Thomas
T
Osterborg
Anders
A
Nilsson
Kenneth
K
Oberg
Fredrik
F
Jernberg Wiklund
Helena
H
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D015850:Interleukin-6; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology*; D050796:STAT3 Transcription Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D015534:Trans-Activators / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007372:Interferons; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases