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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

HDAC pharmacological inhibition promotes cell death through the eIF2α kinases PKR and GCN2

Philippos Peidis1, Andreas I Papadakis, Kamindla Rajesh

  • 1Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada. filippos.peidis@mail.mcgill.ca

Aging
|November 16, 2010
PubMed

Insights

Histone deacetylase inhibitors (HDACi) induce eIF2α phosphorylation via multiple kinases. While eIF2α phosphorylation is protective, specific kinases like PKR and GCN2 promote apoptosis, revealing a dual role in HDACi therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Histone deacetylase inhibitors (HDACi) are used clinically for cutaneous T-cell lymphoma and investigated for other cancers.
  • Previous studies indicate that HDACi treatment induces eIF2α phosphorylation, but the responsible kinase and biological significance remain unclear.

Purpose of the Study:

  • To identify the kinases responsible for eIF2α phosphorylation induced by HDACi.
  • To elucidate the biological role of eIF2α phosphorylation in response to HDACi treatment.

Main Methods:

  • Treatment of cells with the HDACi vorinostat.
  • Analysis of eIF2α phosphorylation levels.
  • Investigation of the roles of specific eIF2α kinases (PKR, GCN2) in response to vorinostat.

Main Results:

  • eIF2α phosphorylation upon vorinostat treatment is not mediated by a single kinase; multiple eIF2α kinases contribute to its upregulation.
  • eIF2α phosphorylation exhibits a cytoprotective effect.
  • The eIF2α kinases PKR and GCN2 actively promote vorinostat-induced apoptosis.

Conclusions:

  • eIF2α kinases display a dual role in the context of HDAC inhibitor therapy.
  • Understanding this dual nature could have significant implications for optimizing HDACi-based cancer treatments.

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