title: IRF-1 inhibits NF-κB activity, suppresses TRAF2 and cIAP1 and induces breast cancer cell specific growth inhibition.
abstract: Interferon Regulatory Factor (IRF)-1, originally identified as a transcription factor of the human interferon (IFN)-β gene, mediates tumor suppression and may inhibit oncogenesis. We have shown that IRF-1 in human breast cancer cells results in the down-regulation of survivin, tumor cell death, and the inhibition of tumor growth in vivo in xenogeneic mouse models. In this current report, we initiate studies comparing the effect of IRF-1 in human nonmalignant breast cell and breast cancer cell lines. While IRF-1 in breast cancer cells results in growth inhibition and cell death, profound growth inhibition and cell death are not observed in nonmalignant human breast cells. We show that TNF-α or IFN-γ induces IRF-1 in breast cancer cells and results in enhanced cell death. Abrogation of IRF-1 diminishes TNF-α and IFN-γ-induced apoptosis. We test the hypothesis that IRF-1 augments TNF-α-induced apoptosis in breast cancer cells. Potential signaling networks elicited by IRF-1 are investigated by evaluating the NF-κB pathway. TNF-α and/or IFN-γ results in decreased presence of NF-κB p65 in the nucleus of breast cancer cells. While TNF-α and/or IFN-γ can induce IRF-1 in nonmalignant breast cells, a marked change in NF-κB p65 is not observed. Moreover, the ectopic expression of IRF-1 in breast cancer cells results in caspase-3, -7, -8 cleavage, inhibits NF-κB activity, and suppresses the expression of molecules involved in the NF-κB pathway. These data show that IRF-1 in human breast cancer cells elicits multiple signaling networks including intrinsic and extrinsic cell death and down-regulates molecules involved in the NF-κB pathway.
authors.affiliation: a Department of Surgery; University of Pittsburgh School of Medicine ; Pittsburgh , PA , USA.
authors.forename: Michaele J
authors.initials: MJ
authors.lastname: Armstrong
authors.forename: Michael T
authors.initials: MT
authors.lastname: Stang
authors.forename: Ye
authors.initials: Y
authors.lastname: Liu
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.forename: Eva
authors.initials: E
authors.lastname: Pizzoferrato
authors.forename: John H
authors.initials: JH
authors.lastname: Yim
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C494257:IRF1 protein, human; D051034:Inhibitor of Apoptosis Proteins; D050856:Interferon Regulatory Factor-1; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D020169:Caspases
keywords: Ad, adenovirus; Cdk, cyclin-dependent kinase; DISC, death-inducing signaling complex; DMEM, Dulbecco's Modified Eagle's Medium; DR, death receptor; EGFP, enhanced green fluorescent protein; ER, estrogen receptor; FADD, fas-associated death domain; FBS, Fetal Bovine Serum; FITC, fluorescein isothiocyanate; FLICE, fas-associated death domain protein interleukin-1 β-converting enzyme; IAP; IFN-β, interferon-β; IFN-γ, interferon-gamma; IKK, IκB, kinase complex; IRF-1; IRF-1, interferon regulatory factor-1; IκB, Inhibitory kappaB; MOI, multiplicity of infection; MTT, methylthiazoltetrazolium; NEMO, NF-κB essential modulator; NF-κB; NF-κB, nuclear factor of kappa Beta; RIP1, receptor interacting protein 1; SCID, severe combined immunodeficiency; STAT, signal transducer and activator of transcription; Smac/DIABLO, Second mitochondria-derived activator of caspase/Direct IAP-binding protein with low pI; TNF-α, tumor necrosis factor-α; TNFR, tumor necrosis factor receptor; TRADD, TNF receptor associated protein with a death domain; TRAF2, tumor necrosis factor receptor-associated factor 2; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; XIAP, X-linked inhibitor of apoptosis protein; apoptosis; breast cancer; cFLIP, cellular FLICE inhibitory protein; cIAP1, c-inhibitor of apoptosis; p53; siRNA, small interfering RNA; tumor suppressor; β-gal, β-galactosidase