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Anti-tumorigenic effects of Type 1 interferon are subdued by integrated stress responses

Oncogene volume 32, pages 4214–4221 (2013)Cite this article

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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.

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Abbreviations

eIF2α:

eukaryotic translation initiation factor 2-α

GCN2:

general control nonrepressed-2

IFN:

interferon

IFNAR1:

interferon-α/β receptor chain 1

ISR:

integrated stress response

MEF:

mouse embryo fibroblast

PERK:

PKR-like ER kinase

PKR:

protein kinase RNA-activated

STAT:

signal transducer and activator of transcription

shRNA:

short hairpin RNA

TG:

thapsigargin.

References

  1. Ye J, Koumenis C . ATF4 an ER stress and hypoxia-inducible transcription factor and its potential role in hypoxia tolerance and tumorigenesis. Curr Mol Med 2009; 9: 411–416.

    Article  CAS  Google Scholar 

  2. Ye J, Kumanova M, Hart LS, Sloane K, Zhang H, De Panis DN et al. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J 2010; 29: 2082–2096.

    Article  CAS  Google Scholar 

  3. Liu Y, Laszlo C, Liu W, Chen X, Evans SC, Wu S . Regulation of G(1) arrest and apoptosis in hypoxia by PERK and GCN2-mediated eIF2alpha phosphorylation. Neoplasia 2010; 12: 61–68.

    Article  CAS  Google Scholar 

  4. Schreiber RD, Old LJ, Smyth MJ . Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011; 331: 1565–1570.

    Article  CAS  Google Scholar 

  5. Moenner M, Pluquet O, Bouchecareilh M, Chevet E . Integrated endoplasmic reticulum stress responses in cancer. Cancer Res 2007; 67: 10631–10634.

    Article  CAS  Google Scholar 

  6. Wek RC, Jiang HY, Anthony TG . Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans 2006; 34 (Pt 1): 7–11.

    Article  CAS  Google Scholar 

  7. Ron D, Walter P . Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007; 8: 519–529.

    Article  CAS  Google Scholar 

  8. Blalock WL, Bavelloni A, Piazzi M, Faenza I, Cocco L . A role for PKR in hematologic malignancies. J Cell Physiol 2010; 223: 572–591.

    CAS  Google Scholar 

  9. Nussbaum JM, Major M, Gunnery S . Transcriptional upregulation of interferon-induced protein kinase, PKR, in breast cancer. Cancer Lett 2003; 196: 207–216.

    Article  CAS  Google Scholar 

  10. Kim SH, Forman AP, Mathews MB, Gunnery S . Human breast cancer cells contain elevated levels and activity of the protein kinase, PKR. Oncogene 2000; 19: 3086–3094.

    Article  CAS  Google Scholar 

  11. Savinova O, Joshi B, Jagus R . Abnormal levels and minimal activity of the dsRNA-activated protein kinase, PKR, in breast carcinoma cells. Int J Biochem Cell Biol 1999; 31: 175–189.

    Article  CAS  Google Scholar 

  12. Bobrovnikova-Marjon E, Grigoriadou C, Pytel D, Zhang F, Ye J, Koumenis C et al. PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene 2010; 29: 3881–3895.

    Article  CAS  Google Scholar 

  13. Koumenis C, Naczki C, Koritzinsky M, Rastani S, Diehl A, Sonenberg N et al. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol Cell Biol 2002; 22: 7405–7416.

    Article  CAS  Google Scholar 

  14. Fels DR, Koumenis C . The PERK/eIF2alpha/ATF4 module of the UPR in hypoxia resistance and tumor growth. Cancer Biol Ther 2006; 5: 723–728.

    Article  CAS  Google Scholar 

  15. Bhattacharya S, HuangFu WC, Liu J, Veeranki S, Baker DP, Koumenis C et al. Inducible priming phosphorylation promotes ligand-independent degradation of the IFNAR1 chain of type I interferon receptor. J Biol Chem 2010; 285: 2318–2325.

    Article  CAS  Google Scholar 

  16. Liu J, HuangFu WC, Kumar KG, Qian J, Casey JP, Hamanaka RB et al. Virus-induced unfolded protein response attenuates antiviral defenses via phosphorylation-dependent degradation of the type I interferon receptor. Cell Host Microbe 2009; 5: 72–83.

    Article  CAS  Google Scholar 

  17. Eggermont AM . The role interferon-alpha in malignant melanoma remains to be defined. Eur J Cancer 2001; 37: 2147–2153.

    Article  CAS  Google Scholar 

  18. Fidler IJ . The organ microenvironment and cancer metastasis. Differentiation 2002; 70: 498–505.

    Article  Google Scholar 

  19. Platanias LC . Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 2005; 5: 375–386.

    Article  CAS  Google Scholar 

  20. Hwang SY, Hertzog PJ, Holland KA, Sumarsono SH, Tymms MJ, Hamilton JA et al. A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses. Proc Natl Acad Sci USA 1995; 92: 11284–11288.

    Article  CAS  Google Scholar 

  21. Bhattacharya S, Zheng H, Tzimas C, Carroll M, Baker DP, Fuchs SY . Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNalpha via accelerating the degradation of its receptor. Blood 2011; 118: 4179–4187.

    Article  CAS  Google Scholar 

  22. Kumar KG, Tang W, Ravindranath AK, Clark WA, Croze E, Fuchs SY . SCF(HOS) ubiquitin ligase mediates the ligand-induced down-regulation of the interferon-alpha receptor. EMBO J 2003; 22: 5480–5490.

    Article  CAS  Google Scholar 

  23. Liu J, Plotnikov A, Banerjee A, Suresh Kumar KG, Ragimbeau J, Marijanovic Z et al. Ligand-independent pathway that controls stability of interferon alpha receptor. Biochem Biophys Res Commun 2008; 367: 388–393.

    Article  CAS  Google Scholar 

  24. Zheng H, Qian J, Carbone CJ, Leu NA, Baker DP, Fuchs SY . Vascular endothelial growth factor-induced elimination of the type 1 interferon receptor is required for efficient angiogenesis. Blood 2011; 118: 4003–4006.

    Article  CAS  Google Scholar 

  25. Zheng H, Qian J, Varghese B, Baker DP, Fuchs S . Ligand-stimulated downregulation of the alpha interferon receptor: role of protein kinase D2. Mol Cell Biol 2011; 31: 710–720.

    Article  CAS  Google Scholar 

  26. Qian J, Zheng H, Huangfu WC, Liu J, Carbone CJ, Leu NA et al. Pathogen recognition receptor signaling accelerates phosphorylation-dependent degradation of IFNAR1. PLoS Pathog 2011; 7: e1002065.

    Article  CAS  Google Scholar 

  27. Bhattacharya S, Qian J, Tzimas C, Baker DP, Koumenis C, Diehl JA et al. Role of p38 protein kinase in the ligand-independent ubiquitination and down-regulation of the IFNAR1 chain of type I interferon receptor. J Biol Chem 2011; 286: 22069–22076.

    Article  CAS  Google Scholar 

  28. Liu J, Carvalho LP, Bhattacharya S, Carbone CJ, Kumar KG, NA Leu et al. Mammalian casein kinase 1alpha and its leishmanial ortholog regulate stability of IFNAR1 and type I interferon signaling. Mol Cell Biol 2009; 29: 6401–6412.

    Article  CAS  Google Scholar 

  29. Huangfu WC, Fuchs SY . Ubiquitination-dependent regulation of signaling receptors in cancer. Genes Cancer 2010; 1: 725–734.

    Article  CAS  Google Scholar 

  30. Diehl JA, Fuchs SY, Koumenis C . The cell biology of the unfolded protein response. Gastroenterology 2011; 141: 38–41 e1-2.

    Article  CAS  Google Scholar 

  31. Bobrovnikova-Marjon E, Pytel D, Riese MJ, Vaites LP, Singh N, Koretzky GA et al. PERK utilizes intrinsic lipid kinase activity to generate phosphatidic acid, mediate AKT activation and promote adipocyte differentiation. Mol Cell Biol 2012; 32: 2268–2278.

    Article  CAS  Google Scholar 

  32. Hamanaka RB, Bobrovnikova-Marjon E, Ji X, Liebhaber SA, Diehl JA . PERK-dependent regulation of IAP translation during ER stress. Oncogene 2009; 28: 910–920.

    Article  CAS  Google Scholar 

  33. Blais JD, Filipenko V, Bi M, Harding HP, Ron D, Koumenis C et al. Activating transcription factor 4 is translationally regulated by hypoxic stress. Mol Cell Biol 2004; 24: 7469–7482.

    Article  CAS  Google Scholar 

  34. Huangfu WC, Qian J, Liu C, Liu J, Lokshin AE, Baker DP et al. Inflammatory signaling compromises cell responses to interferon alpha. Oncogene 2012; 31: 161–172.

    Article  CAS  Google Scholar 

  35. Pindel A, Sadler A . The role of protein kinase R in the interferon response. J Interferon Cytokine Res 2011; 31: 59–70.

    Article  CAS  Google Scholar 

  36. Williams BR . PKR; a sentinel kinase for cellular stress. Oncogene 1999; 18: 6112–6120.

    Article  CAS  Google Scholar 

  37. Pfeffer LM, Wang E, Tamm I . Interferon effects on microfilament organization, cellular fibronectin distribution, and cell motility in human fibroblasts. J Cell Biol 1980; 85: 9–17.

    Article  CAS  Google Scholar 

  38. Brassard DL, Grace MJ, Bordens RW . Interferon-alpha as an immunotherapeutic protein. J Leukoc Biol 2002; 71: 565–581.

    CAS  Google Scholar 

  39. Parmar S, Platanias LC . Interferons: mechanisms of action and clinical applications. Curr Opin Oncol 2003; 15: 431–439.

    Article  CAS  Google Scholar 

  40. Li Y, Srivastava KK, Platanias LC . Mechanisms of type I interferon signaling in normal and malignant cells. Arch Immunol Ther Exp (Warsz) 2004; 52: 156–163.

    CAS  Google Scholar 

  41. Folkman J, Ingber D . Inhibition of angiogenesis. Semin Cancer Biol 1992; 3: 89–96.

    CAS  Google Scholar 

  42. Borovski T, De Sousa EMF, Vermeulen L, Medema JP . Cancer stem cell niche: the place to be. Cancer Res 2011; 71: 634–639.

    Article  CAS  Google Scholar 

  43. Dunn GP, Koebel CM, Schreiber RD . Interferons, immunity and cancer immunoediting. Nat Rev Immunol 2006; 6: 836–848.

    Article  CAS  Google Scholar 

  44. Diamond MS, Kinder M, Matsushita H, Mashayekhi M, Dunn GP, Archambault JM et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med 2011; 208: 1989–2003.

    Article  CAS  Google Scholar 

  45. Fuertes MB, Kacha AK, Kline J, Woo SR, Kranz DM, Murphy KM et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells. J Exp Med 2011; 208: 2005–2016.

    Article  CAS  Google Scholar 

  46. Noman MZ, Messai Y, Carre T, Akalay I, Meron M, Janji B et al. Microenvironmental hypoxia orchestrating the cell stroma cross talk, tumor progression and antitumor response. Crit Rev Immunol 2011; 31: 357–377.

    Article  CAS  Google Scholar 

  47. Tang W, Li Y, Yu D, Thomas-Tikhonenko A, Spiegelman VS, Fuchs SY . Targeting beta-transducin repeat-containing protein E3 ubiquitin ligase augments the effects of antitumor drugs on breast cancer cells. Cancer Res 2005; 65: 1904–1908.

    Article  CAS  Google Scholar 

  48. Soldatenkov VA, Dritschilo A, Ronai Z, Fuchs SY . Inhibition of homologue of Slimb (HOS) function sensitizes human melanoma cells for apoptosis. Cancer Res 1999; 59: 5085–5088.

    CAS  Google Scholar 

  49. Kumar KG, Krolewski JJ, Fuchs SY . Phosphorylation and specific ubiquitin acceptor sites are required for ubiquitination and degradation of the IFNAR1 subunit of type I interferon receptor. J Biol Chem 2004; 279: 46614–46620.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank M Herlyn, R Kaufman, A Koromilas, A Nebreda, D Ron and Z Ronai for reagents, Dr Yong Zhang for technical help, and the members of Fuchs, Diehl and Koumenis labs for discussion. The support to SB from the ‘Training in Tumor Virology’ Grant 2-T32-CA-557726-06 is greatly appreciated. This work was supported by the NIH Grants CA92900 and CA142425 (to SYF), CA94214 (to CK), CA104838 (to JAD) and by a grant with the Pennsylvania Department of Health (to JAD, CK, and SYF). The Department specifically disclaims responsibility for any analyses, interpretation or conclusions.

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  1. Department of Cancer Biology, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Authors and Affiliations

  1. Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

    S Bhattacharya, W-C HuangFu, G Dong, J Qian & S Y Fuchs

  2. Biogen Idec Inc., Cambridge, MA, USA

    D P Baker

  3. Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA

    J Karar & C Koumenis

  4. The Abramson Family Cancer Research Institute, University of Pennsylvania, PA, USA, Philadelphia

    J A Diehl

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  1. S Bhattacharya
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Correspondence to S Y Fuchs.

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Dr DP Baker is an employee of BiogenIDEC Inc. and owns stock of this company. The other authors declare no conflict of interest.

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Bhattacharya, S., HuangFu, WC., Dong, G. et al. Anti-tumorigenic effects of Type 1 interferon are subdued by integrated stress responses. Oncogene 32, 4214–4221 (2013). https://doi.org/10.1038/onc.2012.439

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