Inhibition of interferon-γ-activated nuclear factor-κB by cyclosporin A: A possible mechanism for synergistic induction of apoptosis by interferon-γ and cyclosporin A in gastric carcinoma cells

Kiichiro Beppu, Takashi Morisaki, Hisashi Matsunaga, Akihiko Uchiyama, Eikichi Ihara, Katsuya Hirano, Hideo Kanaide, Masao Tanaka, Mitsuo Katano

研究成果: ジャーナルへの寄稿記事

19 引用 (Scopus)

抄録

We previously reported synergistic induction of apoptosis by IFN-γ plus either cyclosporin A (CsA) or tacrolimus (FK506) in gastric carcinoma cells. In this study, we aimed to elucidate the mechanism for this synergistic induction of apoptosis. IFN-γ plus CsA synergistically induced caspase-3 mediated apoptosis in gastric carcinoma cells. Although IFN-γ induced activation of signal transducer and activator of transcription1 (STAT1) and expression of interferon regulatory factor-1 (IRF-1) mRNA, IFN-γ alone was not able to induce caspase-3 activation and apoptosis. When gastric carcinoma cells were treated with cyclohexamide, a protein synthesis inhibitor, following IFN-γ pretreatment, caspase-3 was activated, and apoptosis was markedly induced. These findings suggest the existence of IFN-γ-induced anti-apoptotic pathway and we evaluated the effect of IFN-γ and CsA on calcium-sensitive nuclear factor-κB (NF-κB) activation. IFN-γ increased intracellular calcium ion concentration ([Ca2+]i) consisting of a spike and a sustained phase, and the latter was completely abrogated by CsA. Activation of NF-κB occurred in response to IFN-γ, and which was markedly inhibited by either CsA or FK506. NF-κB decoy also enhanced the cytotoxic effect of IFN-γ. These results suggest that IFN-γ may simultaneously induce the STAT1-mediated apoptotic pathway and the anti-apoptotic pathway through calcium-activated NF-κB and that inhibition of the latter by CsA may result in dominance of the apoptosis-inducing pathway.

元の言語英語
ページ(範囲)797-805
ページ数9
ジャーナルBiochemical and Biophysical Research Communications
305
発行部数4
DOI
出版物ステータス出版済み - 6 13 2003

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Interferons
Cyclosporine
Stomach
Cells
Apoptosis
Carcinoma
Tacrolimus
Chemical activation
Caspase 3
Calcium
Transducers
Interferon Regulatory Factor-1
Protein Synthesis Inhibitors
Ions
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

これを引用

Inhibition of interferon-γ-activated nuclear factor-κB by cyclosporin A : A possible mechanism for synergistic induction of apoptosis by interferon-γ and cyclosporin A in gastric carcinoma cells. / Beppu, Kiichiro; Morisaki, Takashi; Matsunaga, Hisashi; Uchiyama, Akihiko; Ihara, Eikichi; Hirano, Katsuya; Kanaide, Hideo; Tanaka, Masao; Katano, Mitsuo.

:: Biochemical and Biophysical Research Communications, 巻 305, 番号 4, 13.06.2003, p. 797-805.

研究成果: ジャーナルへの寄稿記事

Beppu, Kiichiro ; Morisaki, Takashi ; Matsunaga, Hisashi ; Uchiyama, Akihiko ; Ihara, Eikichi ; Hirano, Katsuya ; Kanaide, Hideo ; Tanaka, Masao ; Katano, Mitsuo. / Inhibition of interferon-γ-activated nuclear factor-κB by cyclosporin A : A possible mechanism for synergistic induction of apoptosis by interferon-γ and cyclosporin A in gastric carcinoma cells. :: Biochemical and Biophysical Research Communications. 2003 ; 巻 305, 番号 4. pp. 797-805.
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abstract = "We previously reported synergistic induction of apoptosis by IFN-γ plus either cyclosporin A (CsA) or tacrolimus (FK506) in gastric carcinoma cells. In this study, we aimed to elucidate the mechanism for this synergistic induction of apoptosis. IFN-γ plus CsA synergistically induced caspase-3 mediated apoptosis in gastric carcinoma cells. Although IFN-γ induced activation of signal transducer and activator of transcription1 (STAT1) and expression of interferon regulatory factor-1 (IRF-1) mRNA, IFN-γ alone was not able to induce caspase-3 activation and apoptosis. When gastric carcinoma cells were treated with cyclohexamide, a protein synthesis inhibitor, following IFN-γ pretreatment, caspase-3 was activated, and apoptosis was markedly induced. These findings suggest the existence of IFN-γ-induced anti-apoptotic pathway and we evaluated the effect of IFN-γ and CsA on calcium-sensitive nuclear factor-κB (NF-κB) activation. IFN-γ increased intracellular calcium ion concentration ([Ca2+]i) consisting of a spike and a sustained phase, and the latter was completely abrogated by CsA. Activation of NF-κB occurred in response to IFN-γ, and which was markedly inhibited by either CsA or FK506. NF-κB decoy also enhanced the cytotoxic effect of IFN-γ. These results suggest that IFN-γ may simultaneously induce the STAT1-mediated apoptotic pathway and the anti-apoptotic pathway through calcium-activated NF-κB and that inhibition of the latter by CsA may result in dominance of the apoptosis-inducing pathway.",
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T2 - A possible mechanism for synergistic induction of apoptosis by interferon-γ and cyclosporin A in gastric carcinoma cells

AU - Beppu, Kiichiro

AU - Morisaki, Takashi

AU - Matsunaga, Hisashi

AU - Uchiyama, Akihiko

AU - Ihara, Eikichi

AU - Hirano, Katsuya

AU - Kanaide, Hideo

AU - Tanaka, Masao

AU - Katano, Mitsuo

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N2 - We previously reported synergistic induction of apoptosis by IFN-γ plus either cyclosporin A (CsA) or tacrolimus (FK506) in gastric carcinoma cells. In this study, we aimed to elucidate the mechanism for this synergistic induction of apoptosis. IFN-γ plus CsA synergistically induced caspase-3 mediated apoptosis in gastric carcinoma cells. Although IFN-γ induced activation of signal transducer and activator of transcription1 (STAT1) and expression of interferon regulatory factor-1 (IRF-1) mRNA, IFN-γ alone was not able to induce caspase-3 activation and apoptosis. When gastric carcinoma cells were treated with cyclohexamide, a protein synthesis inhibitor, following IFN-γ pretreatment, caspase-3 was activated, and apoptosis was markedly induced. These findings suggest the existence of IFN-γ-induced anti-apoptotic pathway and we evaluated the effect of IFN-γ and CsA on calcium-sensitive nuclear factor-κB (NF-κB) activation. IFN-γ increased intracellular calcium ion concentration ([Ca2+]i) consisting of a spike and a sustained phase, and the latter was completely abrogated by CsA. Activation of NF-κB occurred in response to IFN-γ, and which was markedly inhibited by either CsA or FK506. NF-κB decoy also enhanced the cytotoxic effect of IFN-γ. These results suggest that IFN-γ may simultaneously induce the STAT1-mediated apoptotic pathway and the anti-apoptotic pathway through calcium-activated NF-κB and that inhibition of the latter by CsA may result in dominance of the apoptosis-inducing pathway.

AB - We previously reported synergistic induction of apoptosis by IFN-γ plus either cyclosporin A (CsA) or tacrolimus (FK506) in gastric carcinoma cells. In this study, we aimed to elucidate the mechanism for this synergistic induction of apoptosis. IFN-γ plus CsA synergistically induced caspase-3 mediated apoptosis in gastric carcinoma cells. Although IFN-γ induced activation of signal transducer and activator of transcription1 (STAT1) and expression of interferon regulatory factor-1 (IRF-1) mRNA, IFN-γ alone was not able to induce caspase-3 activation and apoptosis. When gastric carcinoma cells were treated with cyclohexamide, a protein synthesis inhibitor, following IFN-γ pretreatment, caspase-3 was activated, and apoptosis was markedly induced. These findings suggest the existence of IFN-γ-induced anti-apoptotic pathway and we evaluated the effect of IFN-γ and CsA on calcium-sensitive nuclear factor-κB (NF-κB) activation. IFN-γ increased intracellular calcium ion concentration ([Ca2+]i) consisting of a spike and a sustained phase, and the latter was completely abrogated by CsA. Activation of NF-κB occurred in response to IFN-γ, and which was markedly inhibited by either CsA or FK506. NF-κB decoy also enhanced the cytotoxic effect of IFN-γ. These results suggest that IFN-γ may simultaneously induce the STAT1-mediated apoptotic pathway and the anti-apoptotic pathway through calcium-activated NF-κB and that inhibition of the latter by CsA may result in dominance of the apoptosis-inducing pathway.

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