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Interferon gamma (IFNgamma ) and tumor necrosis factor alpha synergism in ME-180 cervical cancer cell apoptosis and necrosis. IFNgamma inhibits cytoprotective NF-kappa B through STAT1/IRF-1 pathways

 Kyoungho Suk  ;  Inik Chang  ;  Yun-Hee Kim  ;  Sunshin Kim  ;  Ja Young Kim  ;  Hocheol Kim  ;  Myung-Shik Lee 
 JOURNAL OF BIOLOGICAL CHEMISTRY, Vol.276(16) : 13153-13159, 2001 
Journal Title
Issue Date
Apoptosis/drug effects* ; Caspase 3 ; Caspase 8 ; Caspase 9 ; Caspases/metabolism ; Cell Survival/drug effects ; Cysteine Proteinase Inhibitors/pharmacology ; DNA-Binding Proteins/metabolism* ; Drug Synergism ; Female ; Humans ; Interferon Regulatory Factor-1 ; Interferon-gamma/toxicity* ; NF-kappa B/metabolism* ; Necrosis ; Phosphoproteins/metabolism* ; Ploidies ; Recombinant Proteins/metabolism ; Recombinant Proteins/toxicity ; STAT1 Transcription Factor ; Trans-Activators/metabolism* ; Transcription Factors/metabolism ; Transfection ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/toxicity* ; Uterine Cervical Neoplasms/pathology
We investigated the molecular mechanism of the synergism between interferon gamma (IFNgamma) and tumor necrosis factor alpha (TNFalpha) documented in a variety of biological occasions such as tumor cell death and inflammatory responses. IFNgamma/TNFalpha synergistically induced apoptosis of ME-180 cervical cancer cells. IFNgamma induced STAT1 phosphorylation and interferon regulatory factor 1 (IRF-1) expression. Transfection of phosphorylation-defective STAT1 inhibited IFNgamma/TNFalpha-induced apoptosis, whereas IRF-1 transfection induced susceptibility to TNFalpha. Dominant-negative IkappaBalpha transfection sensitized ME-180 cells to TNFalpha. IFNgamma pretreatment attenuated TNFalpha- or p65-induced NF-kappaB reporter activity, whereas it did not inhibit p65 translocation or DNA binding of NF-kappaB. IRF-1 transfection alone inhibited TNFalpha-induced NF-kappaB activity, which was reversed by coactivator p300 overexpression. Caspases were activated by IFNgamma/TNFalpha combination; however, caspase inhibition did not abrogate IFNgamma/TNFalpha-induced cell death. Instead, caspase inhibitors directed IFNgamma/TNFalpha-treated ME-180 cells to undergo necrosis, as demonstrated by Hoechst 33258/propidium iodide staining and electron microscopy. Taken together, our results indicate that IFNgamma and TNFalpha synergistically act to destroy ME-180 tumor cells by either apoptosis or necrosis, depending on caspase activation, and STAT1/IRF-1 pathways initiated by IFNgamma play a critical role in IFNgamma/TNFalpha synergism by inhibiting cytoprotective NF-kappaB. IFNgamma/TNFalpha synergism appears to activate cell death machinery independently of caspase activation, and caspase activation seems to merely determine the mode of cell death.
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2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Chang, In Ik(장인익)
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