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.
|Number of pages||9|
|Journal||Biochemical and Biophysical Research Communications|
|Publication status||Published - Jun 13 2003|
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology