title: Anti-tumorigenic effects of Type 1 interferon are subdued by integrated stress responses.
abstract: Viral and pharmacological inducers of protein kinase RNA-activated (PKR)-like ER kinase (PERK) were shown to accelerate the phosphorylation-dependent degradation of the IFNAR1 chain of the Type 1 interferon (IFN) receptor and to limit cell sensitivity to IFN. Here we report that hypoxia can elicit these effects in a PERK-dependent manner. The altered fate of IFNAR1 affected by signaling downstream of PERK depends on phosphorylation of eIF2α (eukaryotic translational initiation factor 2-α) and ensuing activation of p38α kinase. Activators of other eIF2α kinases such as PKR or GCN2 (general control nonrepressed-2) are also capable of eliminating IFNAR1 and blunting IFN responses. Modulation of constitutive PKR activity in human breast cancer cells stabilizes IFNAR1 and sensitizes these cells to IFNAR1-dependent anti-tumorigenic effects. Although downregulation of IFNAR1 and impaired IFNAR1 signaling can be elicited in response to amino-acid deficit, the knockdown of GCN2 in melanoma cells reverses these phenotypes. We propose that, in cancer cells and the tumor microenvironment, activation of diverse eIF2α kinases followed by IFNAR1 downregulation enables multiple cellular components of tumor tissue to evade the direct and indirect anti-tumorigenic effects of Type 1 IFN.
authors.affiliation: Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104-4539, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: W-C
authors.initials: WC
authors.lastname: HuangFu
authors.forename: G
authors.initials: G
authors.lastname: Dong
authors.forename: J
authors.initials: J
authors.lastname: Qian
authors.forename: D P
authors.initials: DP
authors.lastname: Baker
authors.forename: J
authors.initials: J
authors.lastname: Karar
authors.forename: C
authors.initials: C
authors.lastname: Koumenis
authors.forename: J A
authors.initials: JA
authors.lastname: Diehl
authors.forename: S Y
authors.initials: SY
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta; C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase