title: Evidence for eIF2α phosphorylation-independent effects of GSK2656157, a novel catalytic inhibitor of PERK with clinical implications.
abstract: 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 α 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-eIF2α 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 eIF2α phosphorylation. Also, GSK2656157 does not always mimic the biological effects of the genetic inactivation of PERK. Furthermore, cells treated with GSK2656157 increase eIF2α phosphorylation as a means to compensate for the loss of PERK. Using human tumor cells impaired in eIF2α phosphorylation, we demonstrate that GSK2656157 induces ER stress-mediated death suggesting that the drug acts independent of the inhibition of eIF2α 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 eIF2α phosphorylation.
authors.affiliation: Lady Davis Institute for Medical Research; McGill University; Sir Mortimer B. Davis-Jewish General Hospital; Montreal, Quebec, Canada.
authors.forename: Jothilatha
authors.initials: J
authors.lastname: Krishnamoorthy
authors.affiliation: Lady Davis Institute for Medical Research; McGill University; Sir Mortimer B. Davis-Jewish General Hospital; Montreal, Quebec, Canada.
authors.forename: Kamindla
authors.initials: K
authors.lastname: Rajesh
authors.affiliation: Lady Davis Institute for Medical Research; McGill University; Sir Mortimer B. Davis-Jewish General Hospital; Montreal, Quebec, Canada.
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Mirzajani
authors.affiliation: Lady Davis Institute for Medical Research; McGill University; Sir Mortimer B. Davis-Jewish General Hospital; Montreal, Quebec, Canada.
authors.forename: Polixenia
authors.initials: P
authors.lastname: Kesoglidou
authors.affiliation: Lady Davis Institute for Medical Research; McGill University; Sir Mortimer B. Davis-Jewish General Hospital; Montreal, Quebec, Canada.
authors.forename: Andreas I
authors.initials: AI
authors.lastname: Papadakis
authors.affiliation: Lady Davis Institute for Medical Research; McGill University; Sir Mortimer B. Davis-Jewish General Hospital; Montreal, Quebec, Canada; Department of Oncology; Faculty of Medicine; McGill University; Montreal, Quebec, Canada.
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000225:Adenine; D000970:Antineoplastic Agents; D015852:Eukaryotic Initiation Factor-2; D007211:Indoles; D047428:Protein Kinase Inhibitors; D019892:eIF-2 Kinase; C000597302:GSK2656157
keywords: PERK/PEK kinase; endoplasmic reticulum stress; mRNA translation; pharmacological inhibitors; protein phosphorylation; translation initiation factor eIF2; tumorigenesis; unfolded protein response