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Analytical and Bioanalytical Chemistry

, Volume 407, Issue 18, pp 5343–5351 | Cite as

Identification of known drugs targeting the endoplasmic reticulum stress response

  • Kun Bi
  • Kana Nishihara
  • Thomas Machleidt
  • Spencer Hermanson
  • Jun Wang
  • Srilatha Sakamuru
  • Ruili Huang
  • Menghang XiaEmail author
Research Paper

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.

Keywords

ATF6 ER stress pathways NPC library qHTS XBP1 

Notes

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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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Kun Bi
    • 1
  • Kana Nishihara
    • 2
    • 3
  • Thomas Machleidt
    • 4
  • Spencer Hermanson
    • 4
  • Jun Wang
    • 4
  • Srilatha Sakamuru
    • 2
  • Ruili Huang
    • 2
  • Menghang Xia
    • 2
    Email author
  1. 1.Life Science Solutions GroupThermo Fisher ScientificRockfordUSA
  2. 2.National Center for Advancing Translational SciencesNational Institutes of HealthBethesdaUSA
  3. 3.Radiation Genetics, Graduate School of MedicineKyoto UniversityKyotoJapan
  4. 4.Promega CorporationFitchburgUSA

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