Journal
CELL CYCLE
Volume 13, Issue 5, Pages 801-806Publisher
LANDES BIOSCIENCE
DOI: 10.4161/cc.27726
Keywords
unfolded protein response; protein phosphorylation; mRNA translation; translation initiation factor eIF2; PERK/PEK kinase; endoplasmic reticulum stress; tumorigenesis; pharmacological inhibitors
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Funding
- Canadian Cancer Society Research Institute (CCSRI)
- Canadian Institutes of Health Research (CIHR)
- Doctoral Frederick Banting and Charles Best Canadian Graduate Scholarship from CIHR
- CIHR
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The endoplasmic reticulum (ER)-resident protein kinase PERK is a major component of the unfolded protein response (UPR), which promotes the adaptation of cells to various forms of stress. PERK phosphorylates the alpha subunit of the translation initiation factor eIF2 at serine 51, a modification that plays a key role in the regulation of mRNA translation in stressed cells. Several studies have demonstrated that the PERK-eIF2 alpha phosphorylation pathway maintains insulin biosynthesis and glucose homeostasis, facilitates tumor formation and decreases the efficacy of tumor treatment with chemotherapeutic drugs. Recently, a selective catalytic PERK inhibitor termed GSK2656157 has been developed with anti-tumor properties in mice. Herein, we provide evidence that inhibition of PERK activity by GSK2656157 does not always correlate with inhibition of eIF2 alpha phosphorylation. Also, GSK2656157 does not always mimic the biological effects of the genetic inactivation of PERK. Furthermore, cells treated with GSK2656157 increase eIF2 alpha phosphorylation as a means to compensate for the loss of PERK. Using human tumor cells impaired in eIF2 alpha phosphorylation, we demonstrate that GSK2656157 induces ER stress-mediated death suggesting that the drug acts independent of the inhibition of eIF2 alpha phosphorylation. We conclude that GSK2656157 might be a useful compound to dissect pathways that compensate for the loss of PERK and/or identify PERK pathways that are independent of eIF2 alpha phosphorylation.
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