Role of IRF-1 and caspase-7 in IFN-gamma enhancement of Fas-mediated apoptosis in ACHN renal cell carcinoma cells.
Caspases exist as zymogens, and are activated by various extracellular stimuli, leading to apoptosis. One such stimulus is Fas/CD95, a member of the tumor necrosis factor receptor family, providing one means of cytotoxic T lymphocyte (CTL)-mediated cell lysis. Clinical evidence has shown that administration of cytokine leads to regression in selected patients with renal cell carcinomas (RCCs). Interferon-gamma (IFN-gamma) indicates its contribution to anti-tumor activity of immune cells. IFN-gamma elicits its effect through the transcription factor signal transducer and activator of transcription-1 (STAT-1), and through interferon regulatory factor-1 (IRF-1), one of the target genes of STAT-1. Our previous study demonstrated an increase in the susceptibility of ACHN cells, established from RCC, to Fas-mediated apoptosis by IFN-gamma, and the inhibition of this effect by the caspase-3 and -7 inhibitor, DEVD-CHO. We demonstrated the following phenomena in IFN-gamma-treated ACHN cells: 1) enhanced transcription of caspase-1, 3 and 7 mRNAs without any change in cleavage of their substrates; 2) increased cleavage DEVD (specific for caspase-3 and 7), but not YVAD (for caspase-1) or DMQD (for caspase-3), after anti-Fas/CD95 MAb treatment; 3) activation of the STAT-1 and IRF-1 pathway; and 4) partial abrogation of the IFN-gamma-induced increase in Fas-mediated apoptosis by antisense IRF-1 oligodeoxynucleotide. These results suggest that IRF-1 plays a pivotal role in the IFN-gamma-mediated-enhancement of Fas/CD95-mediated apoptosis, through regulation of DEVD-CHO-sensitive caspases, most likely caspase-7.
Tomita
Yoshihiko
Y
Division of Molecular Oncology, Department of Signal Transduction Research, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. ytomita@med.niigata-u.ac.jp
Bilim
Vladimir
V
Hara
Noboru
N
Kasahara
Takashi
T
Takahashi
Kota
K
D017209:Apoptosis / Q000187:drug effects*; D002292:Carcinoma, Renal Cell / Q000473:pathology / Q000628:therapy*; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000473:pathology / Q000628:therapy*; D010750:Phosphoproteins / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000502:physiology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology*
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D010750:Phosphoproteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D019014:fas Receptor; D007371:Interferon-gamma; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases