Krishnamoorthy Jothilatha, Rajesh Kamindla, Mirzajani Farzaneh, Kesoglidou Polixenia, Papadakis Andreas I, Koromilas Antonis E
Lady Davis Institute for Medical Research; McGill University; Sir Mortimer B. Davis-Jewish General Hospital; Montreal, Quebec, Canada.
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.
Cell Cycle. 2014;13(5):801-6. doi: 10.4161/cc.27726. Epub 2014 Jan 8.
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.
内质网（ER）驻留蛋白激酶PERK是未折叠蛋白反应（UPR）的主要组成部分，它促进细胞对各种形式应激的适应。PERK在丝氨酸51位点磷酸化翻译起始因子eIF2的α亚基，这种修饰在应激细胞中mRNA翻译的调节中起关键作用。多项研究表明，PERK-eIF2α磷酸化途径维持胰岛素生物合成和葡萄糖稳态，促进肿瘤形成，并降低化疗药物治疗肿瘤的疗效。最近，一种名为GSK2656157的选择性催化PERK抑制剂已被开发出来，在小鼠中具有抗肿瘤特性。在此，我们提供证据表明，GSK2656157对PERK活性的抑制并不总是与eIF2α磷酸化的抑制相关。此外，GSK2656157并不总是模拟PERK基因失活的生物学效应。此外，用GSK2656157处理的细胞会增加eIF2α磷酸化，作为补偿PERK缺失的一种方式。利用eIF2α磷酸化受损的人类肿瘤细胞，我们证明GSK2656157诱导内质网应激介导的死亡，表明该药物的作用独立于对eIF2α磷酸化的抑制。我们得出结论，GSK2656157可能是一种有用的化合物，可用于剖析补偿PERK缺失的途径和/或识别独立于eIF2α磷酸化的PERK途径。
