Research Paper Volume 2, Issue 10 pp 669—677
HDAC pharmacological inhibition promotes cell death through the eIF2α kinases PKR and GCN2
- 1 Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada
- 2 Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec H3A 1A3, Canada
- 3 Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec H2W 1S6, Canada
Received: September 14, 2010 Accepted: October 29, 2010 Published: October 31, 2010
https://doi.org/10.18632/aging.100216How to Cite
Abstract
Histone deacetylase inhibitors (HDACi) comprise a family of chemotherapeutic agents used in the clinic to treat cutaneous T-cell lymphoma and tested for the therapy of other malignancies. Previous reports have shown that eIF2α phosphorylation is induced upon treatment with HDACi. However the kinase responsible for this phosphorylation or the biological significance of this finding is not yet established. Herein, we show that eIF2α phosphorylation is not attributed to a specific eIF2α kinase, but rather different eIF2α kinases contribute to its upregulation in response to the HDACi, vorinostat. More importantly our data indicate that eIF2α phosphorylation acts in a cytoprotective manner, whereas the eIF2α kinases PKR and GCN2 promote vorinostat-induced apoptosis. These results reveal a dual nature for eIF2α kinases with potential implications in the treatment with histone deacetylase inhibitors.
Abbreviations
Bcr-abl: breakpoint cluster region-abelson; DMSO: dimethyl sulphoxide; dsRNA: double-stranded RNA; eIF2α: eukaryotic initiation factor 2 subunit alpha; eIF2B: eukaryotic initiation factor 2B; ER: endoplasmic reticulum; FACS: fluorescence-activated cell sorting; FADD: Fas-associated protein with death domain; FDA: food and drug administration; FIP1L1-PDGFRA: Fip1-like1-platelet-derived growth factor receptor alpha; GCN2: general control non-derepressible 2; hsp90: heat shock protein 90; GRP78: glucose-regulated protein 78; HCV: hepatitis C virus; HDACi: histone deacetylase inhibitors; HPV: human papillomavirus; HRI: heme-regulated inhibitor; IKK: inhibitor of kappa B kinase; JNK: c-jun NH2-terminal kinase; MEF: mouse embryonic fibroblast; PERK: PKR-like endoplasmic reticulum-resident kinase; PI: propidium iodide; PKR: double-stranded RNA-dependent protein kinase; SAHA: suberoylanilide hydroxamic acid; TNF: tumor necrosis factor; TSA: trichostatin A.