title: BID is a critical factor controlling cell viability regulated by IFN-α.
abstract: Clinical applications of human interferon (IFN)-α have met with varying degrees of success. Nevertheless, key molecules in cell viability regulated by IFN-α have not been clearly identified. Our previous study indicated that IFN (α, β, and ω) receptor (IFNAR) 1/2- and IFN regulatory factor 9-RNA interference (RNAi) completely restored cell viability after IFN-α treatment in human ovarian adenocarcinoma OVCAR3 cells sensitive to IFN-α. In this study, IFNAR1/2- and IFN regulatory factor 9-RNAi inhibited the gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), but not of Fas ligand, after IFN-α treatment. In fact, TRAIL but not Fas ligand inhibited the viability of OVCAR3 cells. IFN-α notably upregulated the levels of TRAIL protein in the supernatant and on the membrane of OVCAR3 cells. After TRAIL signaling, caspase 8 inhibitor and BH3 interacting domain death agonist (BID)-RNAi significantly restored cell viability in response to IFN-α and TRAIL in OVCAR3 cells. Furthermore, BID-RNAi prevented both IFN-α and TRAIL from collapsing the mitochondrial membrane potential (ΔΨm). Finally, we provided important evidence that BID overexpression led to significant inhibition of cell viability after IFN-α or TRAIL treatments in human lung carcinoma A549 cells resistant to IFN-α. Thus, this study suggests that BID is crucial for cell viability regulated by IFN-α which can induce mitochondria-mediated apoptosis, indicating a notable potential to be a targeted therapy for IFN-α resistant tumors.
authors: Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Cytokine Biology Section, NIH, Bethesda, MD, USA.
authors: Takaya
authors: T
authors: Tsuno
authors: Josef
authors: J
authors: Mejido
authors: Tongmao
authors: T
authors: Zhao
authors: Terry
authors: T
authors: Phillips
authors: Timothy G
authors: TG
authors: Myers
authors: Joseph
authors: J
authors: Bekisz
authors: Kathryn C
authors: KC
authors: Zoon
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D053633:Receptor, Interferon alpha-beta