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Introduction: The Unfolded Protein Response

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The Unfolded Protein Response in Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

The translation and appropriate folding of proteins is critical for the maintenance of cellular function. This process is tightly controlled, and it can create a significant energy demand, particularly in secretory cells. Inadequate folding of proteins, as may occur with an insufficient energy supply, can cause unfolded, misfolded, or damaged proteins to accumulate in the endoplasmic reticulum. The consequent endoplasmic reticulum stress leads to activation of the unfolded protein response (UPR). In stressed mitochondria, a similar process is activated (mitochondrial unfolded protein response). The unfolded protein response is an ancient stress response that coordinates multiple functions in an attempt to restore metabolic homeostasis. In higher organisms, three signaling arms, driven respectively by PERK, ATF6, and IRE1α, may be activated. Together, the signaling from these arms coordinates specific cellular functions including autophagy, cell metabolism, and apoptosis. From a cell fate perspective, the outcome of activating the unfolded protein response can be either the restoration of homeostasis and normal cell function, or the failure to do so leading to aberrant cellular function (including neoplastic transformation) and/or the eventual initiation of an irreversible programmed cell death. Hence, activation of the unfolded proteins response can be either prosurvival or prodeath. This book covers many aspects of the unfolded protein response, from its roles in normal cell development and some aspects of immunity, through to those associated with neoplastic transformation and drug resistance in cancer. Also included is a chapter on the role of UPR-activated autophagy in specific neurodegenerative disorders. The primary focus of these chapters is the unfolded protein response as activated by an endoplasmic reticulum stress. While each chapter may be read independently, the reader will gain a much broader perspective of the critical roles of the unfolded protein response when the chapters are read collectively.

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References

  1. Jovaisaite V, Auwerx J. The mitochondrial unfolded protein response-synchronizing genomes. Curr Opin Cell Biol. 2015;33:74–81.

    Article  CAS  Google Scholar 

  2. Arnould T, Michel S, Renard P. Mitochondria retrograde signaling and the UPR mt: where are we in mammals? Int J Mol Sci. 2015;16:18224–51.

    Article  CAS  Google Scholar 

  3. Hollien J. Evolution of the unfolded protein response. Biochim Biophys Acta. 2013;1833:2458–63.

    Article  CAS  Google Scholar 

  4. Clarke R, Cook KL, Hu R, Facey CO, Tavassoly I, Schwartz JL, Baumann WT, Tyson JJ, Xuan J, Wang Y, Warri A, Shajahan AN. Endoplasmic reticulum stress, the unfolded protein response, autophagy, and the integrated regulation of breast cancer cell fate. Cancer Res. 2012;72:1321–31.

    Article  CAS  Google Scholar 

  5. Shim SM, Choi HR, Sung KW, Lee YJ, Kim ST, Kim D, Mun SR, Hwang J, Cha-Molstad H, Ciechanover A, Kim BY, Kwon YT. The endoplasmic reticulum-residing chaperone BiP is short-lived and metabolized through N-terminal arginylation. Sci Signal. 2018;11. pii: eaan0630.

    Google Scholar 

  6. Morito D, Hirao K, Oda Y, Hosokawa N, Tokunaga F, Cyr DM, Tanaka K, Iwai K, Nagata K. Gp78 cooperates with RMA1 in endoplasmic reticulum-associated degradation of CFTRDeltaF508. Mol Biol Cell. 2008;19:1328–36.

    Article  CAS  Google Scholar 

  7. Buchberger A, Bukau B, Sommer T. Protein quality control in the cytosol and the endoplasmic reticulum: brothers in arms. Mol Cell. 2010;40:238–52.

    Article  CAS  Google Scholar 

  8. Shiber A, Ravid T. Chaperoning proteins for destruction: diverse roles of Hsp70 chaperones and their co-chaperones in targeting misfolded proteins to the proteasome. Biomol Ther. 2014;4:704–24.

    Google Scholar 

  9. Ding WX, Yin XM. Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome. Autophagy. 2008;4:141–50.

    Article  CAS  Google Scholar 

  10. Clarke R, Shajahan AN, Wang Y, Tyson JJ, Riggins R, Weiner LM, Baumann WT, Xuan J, Zhang B, Facey C, Aiyer H, Cook K, Hickman FE, Tavassoly I, Verdugo A, Chen C, Zwart A, Wärri A, Hilakivi-Clarke LA. Endoplasmic reticulum stress, the unfolded protein response, and gene network modeling in antiestrogen resistant breast cancer. Horm Mol Biol Clin Invest. 2011;5:35–44.

    CAS  Google Scholar 

  11. Back SH, Kaufman RJ. Endoplasmic reticulum stress and type 2 diabetes. Annu Rev Biochem. 2012;81:767–93.

    Article  CAS  Google Scholar 

  12. Scheuner D, Kaufman RJ. The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes. Endocr Rev. 2008;29:317–33.

    Article  CAS  Google Scholar 

  13. Mohrin M, Widjaja A, Liu Y, Luo H, Chen D. The mitochondrial unfolded protein response is activated upon hematopoietic stem cell exit from quiescence. Aging Cell. 2018;17:e12756.

    Article  Google Scholar 

  14. Sigurdsson V, Miharada K. Regulation of unfolded protein response in hematopoietic stem cells. Int J Hematol. 2018;107:627.

    Article  CAS  Google Scholar 

  15. Scheckel C, Aguzzi A. Prions, prionoids and protein misfolding disorders. Nat Rev Genet. 2018;19:405–18.

    Article  CAS  Google Scholar 

  16. Tyson JJ, Baumann WT, Chen C, Verdugo A, Tavassoly I, Wang Y, Weiner LM, Clarke R. Dynamic modeling of oestrogen signalling and cell fate in breast cancer cells. Nat Rev Cancer. 2011;11:523–32.

    Article  CAS  Google Scholar 

  17. Rajapaksa G, Thomas C, Gustafsson JA. Estrogen signaling and unfolded protein response in breast cancer. J Steroid Biochem Mol Biol. 2016;163:45–50.

    Article  CAS  Google Scholar 

  18. Livezey M, Kim JE, Shapiro DJ. A new role for estrogen receptor alpha in cell proliferation and cancer: activating the anticipatory unfolded protein response. Front Endocrinol. 2018;9:325.

    Google Scholar 

  19. Vihervaara A, Duarte FM, Lis JT. Molecular mechanisms driving transcriptional stress responses. Nat Rev Genet. 2018;19:385–97.

    Article  CAS  Google Scholar 

  20. Kondratyev M, Avezov E, Shenkman M, Groisman B, Lederkremer GZ. PERK-dependent compartmentalization of ERAD and unfolded protein response machineries during ER stress. Exp Cell Res. 2007;313:3395–407.

    Article  CAS  Google Scholar 

  21. Tsai YC, Weissman AM. The unfolded protein response, degradation from endoplasmic reticulum and cancer. Genes Cancer. 2010;1:764–78.

    Article  CAS  Google Scholar 

  22. Kleiger G, Mayor T. Perilous journey: a tour of the ubiquitin-proteasome system. Trends Cell Biol. 2014;24:352–9.

    Article  CAS  Google Scholar 

  23. Kaushik S, Cuervo AM. The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol. 2018;19:365–81.

    Article  CAS  Google Scholar 

  24. Fujita E, Kouroku Y, Isoai A, Kumagai H, Misutani A, Matsuda C, Hayashi YK, Momoi T. Two endoplasmic reticulum-associated degradation (ERAD) systems for the novel variant of the mutant dysferlin: ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II). Hum Mol Genet. 2007;16:618–29.

    Article  CAS  Google Scholar 

  25. Obacz J, Avril T, Le Reste PJ, Urra H, Quillien V, Hetz C, Chevet E. Endoplasmic reticulum proteostasis in glioblastoma-from molecular mechanisms to therapeutic perspectives. Sci Signal. 2017;10. pii: eaal2323.

    Google Scholar 

  26. Dominicus CS, Patel V, Chambers JE, Malzer E, Marciniak SJ. Endoplasmic reticulum stress signaling during development. In: Clarke R, editor. Introduction to the unfolded protein response. New York: Springer; 2018.

    Google Scholar 

  27. Arensdorf AM, Diedrichs D, Rutkowski DT. Regulation of the transcriptome by ER stress: non-canonical mechanisms and physiological consequences. Front Genet. 2013;4:256.

    PubMed  PubMed Central  Google Scholar 

  28. Morreal J, Hong F, Li Z. Regulation of the unfolded protein response and its roles in tumorigenesis and cancer therapy. In: Clarke R, editor. Introduction to the unfolded protein response. New York: Springer; 2018.

    Google Scholar 

  29. Bu Y, Diehl JA. PERK integrates oncogenic signaling and cell survival during cancer development. J Cell Physiol. 2016;231:2088–96.

    Article  CAS  Google Scholar 

  30. Xie H, Tang CH, Song JH, Mancuso A, Del Valle JR, Cao J, Xiang Y, Dang CV, Lan R, Sanchez DJ, Keith B, Hu CC, Simon MC. IRE1alpha RNase-dependent lipid homeostasis promotes survival in Myc-transformed cancers. J Clin Invest. 2018;128:1300–16.

    Article  Google Scholar 

  31. Shajahan-Haq AN, Cook KL, Schwartz-Roberts JL, Eltayeb AE, Demas DM, Warri AM, Facey CO, Hilakivi-Clarke LA, Clarke R. MYC regulates the unfolded protein response and glucose and glutamine uptake in endocrine resistant breast cancer. Mol Cancer. 2014;13:239.

    Article  Google Scholar 

  32. Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia. 2015;3:83–92.

    Article  Google Scholar 

  33. Fels DR, Koumenis C. The PERK/eIF2alpha/ATF4 module of the UPR in hypoxia resistance and tumor growth. Cancer Biol Ther. 2006;5:723–8.

    Article  CAS  Google Scholar 

  34. Singleton DC, Harris AL. ATF4, hypoxia and treatment resistance in cancer. In: Clarke R, editor. Introduction to the unfolded protein response. New York: Springer; 2018.

    Google Scholar 

  35. Sengupta S, Jordan VC, Clarke R. Role of protein translation in the unfolded protein response. In: Clarke R, editor. Introduction to the unfolded protein response. New York: Springer; 2018.

    Google Scholar 

  36. Aarti I, Rajesh K, Ramaiah KV. Phosphorylation of eIF2 alpha in Sf9 cells: a stress, survival and suicidal signal. Apoptosis. 2010;15:679–92.

    Article  CAS  Google Scholar 

  37. Hu R, Clarke R. Roles of spliced and unspliced XBP1 in breast cancer. In: Clarke R, editor. Introduction to the unfolded protein response. New York: Springer; 2018.

    Google Scholar 

  38. Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol. 2016;13:674–90.

    Article  CAS  Google Scholar 

  39. Jamdade VS, Sethi N, Mundhe NA, Kumar P, Lahkar M, Sinha N. Therapeutic targets of triple-negative breast cancer: a review. Br J Pharmacol. 2015;172:4228–37.

    Article  CAS  Google Scholar 

  40. Zhao N, Peng F, Chen X. The unfolded protein response in triple-negative breast cancer. In: Clarke R, editor. Introduction to the unfolded protein response. New York: Springer; 2018.

    Google Scholar 

  41. Clarke R, Tyson JJ, Dixon JM. Endocrine resistance in breast cancer – an overview and update. Mol Cell Endocrinol. 2015;418:220–34.

    Article  CAS  Google Scholar 

  42. Clarke R. The unfolded protein response as an integrator of response to endocrine therapy in estrogen receptor positive breast cancer. In: Clarke R, editor. Introduction to the unfolded protein response. New York: Springer; 2018.

    Google Scholar 

  43. Cook KL. Outside the endoplasmic reticulum: non-canonical GRP78 signaling. In: Clarke R, editor. Introduction to the unfolded protein response. New York: Springer; 2018.

    Google Scholar 

  44. Schwarze S, Rangnekar VM. Targeting plasma membrane GRP78 for cancer growth inhibition. Cancer Biol Ther. 2010;9:153–5.

    Article  CAS  Google Scholar 

  45. Pommier A, Anaparthy N, Memos N, Kelley ZL, Gouronnec A, Yan R, Auffray C, Albrengues J, Egeblad M, Iacobuzio-Donahue CA, Lyons SK, Fearon DT. Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases. Science. 2018;360. pii: eaao4908.

    Google Scholar 

  46. Scheper W, Hoozemans JJ. The unfolded protein response in neurodegenerative diseases: a neuropathological perspective. Acta Neuropathol. 2015;130:315–31.

    Article  CAS  Google Scholar 

  47. Scheper W, Hoozemans JJ. A new PERKspective on neurodegeneration. Sci Transl Med. 2013;5:206fs37.

    Article  Google Scholar 

  48. Hughes D, Mallucci GR. The unfolded protein response in neurodegenerative disorders - therapeutic modulation of the PERK pathway. FEBS J. 2018.

    Google Scholar 

  49. Moussa C. Autophagy and the unfolded protein response in neurodegenerative diseases. In: Clarke R, editor. Introduction to the unfolded protein response. New York: Springer; 2018.

    Google Scholar 

  50. Clarke, R., Tyson, J. J., Tan, M., Baumann, W. T., Xuan, J., and Wang, Y. Systems biology: perspectives on multiscale modeling in research on endocrine-related cancers. Endocr Relat Cancer. 2018; in revision.

    Google Scholar 

  51. Parmar JH, Cook KL, Shajahan-Haq AN, Clarke PA, Tavassoly I, Clarke R, Tyson JJ, Baumann WT. Modelling the effect of GRP78 on anti-oestrogen sensitivity and resistance in breast cancer. Interface Focus. 2013;3:20130012.

    Article  Google Scholar 

  52. Ma’ayan A. Insights into the organization of biochemical regulatory networks using graph theory analyses. J Biol Chem. 2009;284:5451–5.

    Article  Google Scholar 

  53. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334:1081–6.

    Article  CAS  Google Scholar 

  54. Shapiro DJ, Livezey M, Yu L, Zheng X, Andruska N. Anticipatory UPR activation: a protective pathway and target in Cancer. Trends Endocrinol Metab. 2016;27:731–41.

    Article  CAS  Google Scholar 

  55. Nargund AM, Fiorese CJ, Pellegrino MW, Deng P, Haynes CM. Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt). Mol Cell. 2015;58:123–33.

    Article  CAS  Google Scholar 

  56. Pellegrino MW, Nargund AM, Kirienko NV, Gillis R, Fiorese CJ, Haynes CM. Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection. Nature. 2014;516:414–7.

    Article  CAS  Google Scholar 

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  1. Department of Oncology, Georgetown University Medical Center, Washington, DC, USA

    Robert Clarke

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  1. Department of Oncology, Georgetown University Medical Center, Washington, DC, USA

    Robert Clarke

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Clarke, R. (2019). Introduction: The Unfolded Protein Response. In: Clarke, R. (eds) The Unfolded Protein Response in Cancer. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-030-05067-2_1

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  • DOI: https://doi.org/10.1007/978-3-030-05067-2_1

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  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-030-05065-8

  • Online ISBN: 978-3-030-05067-2

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