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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

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TRAIL-induced variation of cell signaling states provides nonheritable resistance to apoptosis

Reema Baskar1,2, Harris G Fienberg2,3, Zumana Khair2

  • 1Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.

Life Science Alliance
|November 10, 2019
PubMed

Insights

Tumor necrosis factor-alpha (TNFα)-related apoptosis-inducing ligand (TRAIL) therapy shows fractional cancer cell killing due to signaling diversity. Blocking this diversity and subsequent translation enhances TRAIL

Area of Science:

  • Cell biology
  • Immunology
  • Cancer research

Background:

  • Tumor necrosis factor-alpha (TNFα)-related apoptosis-inducing ligand (TRAIL) therapy aims to induce programmed cell death in cancer cells.
  • TRAIL therapy often results in fractional killing, failing to eradicate all cancer cells, which limits its clinical efficacy.
  • This incomplete cell death is attributed to cellular heterogeneity that bulk assays cannot resolve.

Purpose of the Study:

  • To quantify the diversity in cellular signaling responses to TRAIL using single-cell mass cytometry (CyTOF).
  • To link this signaling diversity to the frequency of apoptotic resistance in various cell systems.
  • To investigate mechanisms underlying nonheritable fractional escape from TRAIL-induced apoptosis.

Main Methods:

  • Single-cell mass cytometry (CyTOF) was employed to measure cellular signaling responses to TRAIL.
  • Kinase inhibitors were used to constrict signaling variation.
  • Cycloheximide was utilized to block de novo protein translation in resistant cells.

Main Results:

  • All cells responded to TRAIL, but a variable fraction exhibited resistance to apoptosis.
  • Signaling diversity upon TRAIL exposure correlated with TRAIL resistance.
  • Constricting signaling variation with kinase inhibitors reduced TRAIL resistance.
  • Blocking TRAIL-induced de novo translation in resistant cells abrogated resistance.

Conclusions:

  • Cellular signaling diversity is intrinsically linked to nonheritable fractional escape from TRAIL-induced apoptosis.
  • Targeting signaling diversity and subsequent translation represents a promising strategy to overcome TRAIL resistance in cancer therapy.
  • This study provides a refined understanding of TRAIL resistance mechanisms, opening new avenues for death ligand-based therapies.

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