Indirubin Inhibits TRAIL-Induced Activation of Death Receptor 5 in Jurkat Cells

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Abstract

Death receptor 5 (DR5) is an apoptosis-inducing membrane receptor that mediates cell death in several life-threatening conditions. There is a crucial need for the discovery of DR5 antagonists for the therapeutic intervention of conditions in which the overactivation of DR5 underlies the pathophysiology. DR5 activation mediates cell death in non-alcoholic fatty liver disease (NAFLD) and neurodegenerative processes including amyloid-beta (Aβ) accumulation, spinal cord injury (SCI), and brain ischemia. In the current work, we used fluorescence resonance energy transfer (FRET) to monitor the conformational dynamics of DR5 that mediate death signaling. We used a time-resolved FRET screening platform to screen the Selleck library of 2863 U.S. Food and Drug Administration (FDA)-approved compounds. The high-throughput screen (HTS) identified 13 compounds that modulated the FRET between DR5 monomers beyond 5 median absolute deviations (MADs) from the DMSO controls. Of these 13 compounds, indirubin was identified to specifically inhibit tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced caspase-8 activity without modulating DR5 surface expression or TRAIL binding. Indirubin inhibited Fas-associated death domain (FADD) oligomerization and increased cellular FLICE-inhibitory protein (c-FLIP) expression; both are molecular mechanisms involved in inhibiting the DR5 signaling cascade. This study has elucidated previously unknown properties of indirubin that make it a promising candidate for therapeutic investigation of diseases in which overactivation of DR5 underlies pathology.

Original languageEnglish (US)
JournalNatural Product Communications
Volume18
Issue number1
DOIs
StatePublished - Jan 2023

Bibliographical note

Funding Information:
The first author would like to thank Dr Nagamani Vunnam, Dr Samantha Yuen, and Dr Robyn Rebbeck for the continuous support, mentorship, and training on this project. The progress made here would not be possible without their intellect, talent, and kindness. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Heart, Lung, and Blood Institute and National Institutes of Health (grant numbers R01HL139065 and R35GM131814)

Funding Information:
This work was supported by the Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX22_0931).

Publisher Copyright:
© The Author(s) 2022.

Keywords

  • alkaloid
  • death receptor 5
  • high-throughput screening
  • indirubin
  • TRAIL

PubMed: MeSH publication types

  • Journal Article

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