title: Resistance to IFN-alpha-induced apoptosis is linked to a loss of STAT2.
abstract: Type I IFNs (IFN-alpha/beta) are pleitropic cytokines widely used in the treatment of certain malignancies, hepatitis B and C, and multiple sclerosis. IFN resistance is a challenging clinical problem to overcome. Hence, understanding the molecular mechanism by which IFN immunotherapy ceases to be effective is of translational importance. In this study, we report that continuous IFN-alpha stimulation of the human Jurkat variant H123 led to resistance to type I IFN-induced apoptosis due to a loss of signal transducers and activators of transcription 2 (STAT2) expression. The apoptotic effects of IFN-alpha were hampered as STAT2-deficient cells were defective in activating the mitochondrial-dependent death pathway and ISGF3-mediated gene activation. Reconstitution of STAT2 restored the apoptotic effects of IFN-alpha as measured by the loss of mitochondrial membrane potential, cytochrome c release from mitochondria, caspase activation, and ultimately cell death. Nuclear localization of STAT2 was a critical event as retention of tyrosine-phosphorylated STAT2 in the cytosol was not sufficient to activate apoptosis. Furthermore, silencing STAT2 gene expression in Saos2 and A375S.2 tumor cell lines significantly reduced the apoptotic capacity of IFN-alpha. Altogether, we show that STAT2 is a critical mediator in the activation of type I IFN-induced apoptosis. More importantly, defects in the expression or nuclear localization of STAT2 could lessen the efficacy of type I IFN immunotherapy.
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, Maryland, USA.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Romero-Weaver
authors.forename: Hsiang-Wen
authors.initials: HW
authors.lastname: Wang
authors.forename: Håkan C
authors.initials: HC
authors.lastname: Steen
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Scarzello
authors.forename: Veronica L
authors.initials: VL
authors.lastname: Hall
authors.forename: Faruk
authors.initials: F
authors.lastname: Sheikh
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Donnelly
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gamero
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D017353:Gene Deletion; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D019169:Jurkat Cells; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D016898:Interferon-alpha; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; D011505:Protein-Tyrosine Kinases