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Identification of known drugs targeting the endoplasmic reticulum stress response

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Abstract

The endoplasmic reticulum (ER), a multifunctional organelle, plays a central role in cellular signaling, development, and stress response. Dysregulation of ER homeostasis has been associated with human diseases, such as cancer, inflammation, and diabetes. A broad spectrum of stressful stimuli including hypoxia as well as a variety of pharmacological agents can lead to the ER stress response. In this study, we have developed a stable ER stress reporter cell line that stably expresses a β-lactamase reporter gene under the control of the ER stress response element (ESRE) present in the glucose-regulated protein, 78 kDa (GRP78) gene promoter. This assay has been optimized and miniaturized into a 1536-well plate format. In order to identify clinically used drugs that induce ER stress response, we screened approximately 2800 drugs from the NIH Chemical Genomics Center Pharmaceutical Collection (NPC library) using a quantitative high-throughput screening (qHTS) platform. From this study, we have identified several known ER stress inducers, such as 17-AAG (via HSP90 inhibition), as well as several novel ER stress inducers such as AMI-193 and spiperone. The confirmed drugs were further studied for their effects on the phosphorylation of eukaryotic initiation factor 2α (eIF2α), the X-box-binding protein (XBP1) splicing, and GRP78 gene expression. These results suggest that the ER stress inducers identified from the NPC library using the qHTS approach could shed new lights on the potential therapeutic targets of these drugs.

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References

  1. Zhang K, Kaufman RJ (2008) From endoplasmic-reticulum stress to the inflammatory response. Nature 454(7203):455–462. doi:10.1038/nature07203

    Article  CAS  Google Scholar 

  2. Kim I, Xu W, Reed JC (2008) Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 7(12):1013–1030

    Article  CAS  Google Scholar 

  3. Ozcan L, Tabas I (2012) Role of endoplasmic reticulum stress in metabolic disease and other disorders. Annu Rev Med 63:317–328

    Article  CAS  Google Scholar 

  4. Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13(2):89–102

    CAS  Google Scholar 

  5. Oakes SA, Papa FR (2015) The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol 10:173–194. doi:10.1146/annurev-pathol-012513-104649

    Article  CAS  Google Scholar 

  6. Dufey E, Sepulveda D, Rojas-Rivera D, Hetz C (2014) Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. 1. An overview. Am J Physiol Cell Physiol 307(7):C582–594. doi:10.1152/ajpcell.00258.2014

    Article  CAS  Google Scholar 

  7. Lee AH, Iwakoshi NN, Anderson KC, Glimcher LH (2003) Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci U S A 100(17):9946–9951

    Article  CAS  Google Scholar 

  8. Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, Yuan J (2005) A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 307(5711):935–939. doi:10.1126/science.1101902

    Article  CAS  Google Scholar 

  9. Rahmani M, Davis EM, Crabtree TR, Habibi JR, Nguyen TK, Dent P, Grant S (2007) The kinase inhibitor sorafenib induces cell death through a process involving induction of endoplasmic reticulum stress. Mol Cell Biol 27(15):5499–5513

    Article  CAS  Google Scholar 

  10. Huang R, Southall N, Wang Y, Yasgar A, Shinn P, Jadhav A, Nguyen DT, Austin CP (2011) The NCGC pharmaceutical collection: a comprehensive resource of clinically approved drugs enabling repurposing and chemical genomics. Sci Transl Med 3(80):80ps16. doi:10.1126/scitranslmed.3001862

    Article  Google Scholar 

  11. Miller SC, Huang R, Sakamuru S, Shukla SJ, Attene-Ramos MS, Shinn P, Van Leer D, Leister W, Austin CP, Xia M (2010) Identification of known drugs that act as inhibitors of NF-kappaB signaling and their mechanism of action. Biochem Pharmacol 79(9):1272–1280. doi:10.1016/j.bcp.2009.12.021

    Article  CAS  Google Scholar 

  12. Zlokarnik G, Negulescu PA, Knapp TE, Mere L, Burres N, Feng L, Whitney M, Roemer K, Tsien RY (1998) Quantitation of transcription and clonal selection of single living cells with beta-lactamase as reporter. Science 279(5347):84–88

    Article  CAS  Google Scholar 

  13. Xia M, Huang R, Guo V, Southall N, Cho MH, Inglese J, Austin CP, Nirenberg M (2009) Identification of compounds that potentiate CREB signaling as possible enhancers of long-term memory. Proc Natl Acad Sci U S A 106(7):2412–2417

    Article  CAS  Google Scholar 

  14. Huang R, Sakamuru S, Martin MT, Reif DM, Judson RS, Houck KA, Casey W, Hsieh JH, Shockley KR, Ceger P, Fostel J, Witt KL, Tong W, Rotroff DM, Zhao T, Shinn P, Simeonov A, Dix DJ, Austin CP, Kavlock RJ, Tice RR, Xia M (2014) Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway. Sci Rep 4:5664. doi:10.1038/srep05664

    CAS  Google Scholar 

  15. Inglese J, Auld DS, Jadhav A, Johnson RL, Simeonov A, Yasgar A, Zheng W, Austin CP (2006) Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries. Proc Natl Acad Sci U S A 103(31):11473–11478. doi:10.1073/pnas.0604348103

    Article  CAS  Google Scholar 

  16. Robers MB, Horton RA, Bercher MR, Vogel KW, Machleidt T (2008) High-throughput cellular assays for regulated posttranslational modifications. Anal Biochem 372(2):189–197. doi:10.1016/j.ab.2007.09.012

    Article  CAS  Google Scholar 

  17. Davenport EL, Moore HE, Dunlop AS, Sharp SY, Workman P, Morgan GJ, Davies FE (2007) Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells. Blood 110(7):2641–2649. doi:10.1182/blood-2006-11-053728

    Article  CAS  Google Scholar 

  18. Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH (2006) Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 107(12):4907–4916. doi:10.1182/blood-2005-08-3531

    Article  CAS  Google Scholar 

  19. Sarro E, Jacobs-Cacha C, Itarte E, Meseguer A (2012) A pharmacologically-based array to identify targets of cyclosporine A-induced toxicity in cultured renal proximal tubule cells. Toxicol Appl Pharmacol 258(2):275–287

    Article  CAS  Google Scholar 

  20. Ciechomska IA, Kaminska B (2012) ER stress and autophagy contribute to CsA-induced death of malignant glioma cells. Autophagy 8(10)

  21. Hansen HC, Olsson R, Croston G, Andersson CM (2000) Multistep solution-phase parallel synthesis of spiperone analogues. Bioorg Med Chem Lett 10(21):2435–2439

    Article  CAS  Google Scholar 

  22. Neutel JM, Smith DH (2013) Hypertension management: rationale for triple therapy based on mechanisms of action. Cardiovasc Ther 31(5):251–258. doi:10.1111/1755-5922.12015

    Article  CAS  Google Scholar 

  23. Grunder G, Wetzel H, Hammes E, Benkert O (1993) Roxindole, a dopamine autoreceptor agonist, in the treatment of major depression. Psychopharmacology (Berlin) 111(1):123–126

    Article  CAS  Google Scholar 

  24. Basso LG, Rodrigues RZ, Naal RM, Costa-Filho AJ (2011) Effects of the antimalarial drug primaquine on the dynamic structure of lipid model membranes. Biochim Biophys Acta 1808(1):55–64. doi:10.1016/j.bbamem.2010.08.009

    Article  CAS  Google Scholar 

  25. Nelson JA, Carpenter JW, Rose LM, Adamson DJ (1975) Mechanisms of action of 6-thioguanine, 6-mercaptopurine, and 8-azaguanine. Cancer Res 35(10):2872–2878

    CAS  Google Scholar 

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Acknowledgments

We thank Sam Michael and Paul Shinn for assistance with automated screening and compound management. These studies were supported by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health.

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Authors and Affiliations

  1. Life Science Solutions Group, Thermo Fisher Scientific, Rockford, IL, 61105, USA

    Kun Bi

  2. National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA

    Kana Nishihara, Srilatha Sakamuru, Ruili Huang & Menghang Xia

  3. Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo, Kyoto, 606-8501, Japan

    Kana Nishihara

  4. Promega Corporation, Fitchburg, WI, 53711, USA

    Thomas Machleidt, Spencer Hermanson & Jun Wang

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  1. Kun Bi
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  2. Kana Nishihara
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  3. Thomas Machleidt
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  4. Spencer Hermanson
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  5. Jun Wang
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  7. Ruili Huang
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  8. Menghang Xia
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Correspondence to Menghang Xia.

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Bi, K., Nishihara, K., Machleidt, T. et al. Identification of known drugs targeting the endoplasmic reticulum stress response. Anal Bioanal Chem 407, 5343–5351 (2015). https://doi.org/10.1007/s00216-015-8694-2

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  • DOI: https://doi.org/10.1007/s00216-015-8694-2

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