Role of IRF-1 and caspase-7 in IFN-gamma enhancement of Fas-mediated apoptosis in ACHN renal cell carcinoma cells

Int J Cancer. 2003 Apr 20;104(4):400-8. doi: 10.1002/ijc.10956.


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.

MeSH terms

  • Apoptosis / drug effects*
  • Carcinoma, Renal Cell / pathology
  • Carcinoma, Renal Cell / therapy*
  • Caspase 3
  • Caspase 7
  • Caspases / genetics
  • Caspases / physiology*
  • DNA-Binding Proteins / physiology*
  • Gene Expression Regulation / drug effects
  • Humans
  • Interferon Regulatory Factor-1
  • Interferon-gamma / pharmacology*
  • Interferon-gamma / therapeutic use
  • Kidney Neoplasms / pathology
  • Kidney Neoplasms / therapy*
  • Phosphoproteins / physiology*
  • RNA, Messenger / analysis
  • STAT1 Transcription Factor
  • Trans-Activators / physiology
  • Tumor Cells, Cultured
  • fas Receptor / physiology*


  • DNA-Binding Proteins
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • Phosphoproteins
  • RNA, Messenger
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Trans-Activators
  • fas Receptor
  • Interferon-gamma
  • CASP3 protein, human
  • CASP7 protein, human
  • Caspase 3
  • Caspase 7
  • Caspases