The eIF2-alpha kinase HRI: a potential target beyond the red blood cell

Abstract

The eIF2α kinase heme-regulated inhibitor (HRI) is one of four well-described kinases that phosphorylate eIF2α in response to various cell stressors, resulting in reduced ternary complex formation and attenuation of mRNA translation. Although HRI is well known for its role as a heme sensor in erythroid progenitors, pharmacologic activation of HRI has been demonstrated to have anti-cancer activity across a wide range of tumor sub-types. Here, the potential of HRI activators as novel cancer therapeutics is explored. Areas covered: We provide an introduction to eIF2 signaling pathways in general, and specifically review data on the eIF2α kinase HRI in erythroid and non-erythroid cells. We review aspects of targeting eIF2 signaling in cancer and highlight promising data using HRI activators against tumor cells. Expert opinion: Pharmacologic activation of HRI inhibits tumor growth as a single agent without appreciable toxicity in vivo. The ability of HRI activators to provide direct and sustained eIF2α phosphorylation without inducing oxidative stress or broad eIF2α kinase activation may be especially advantageous for tolerability. Combination therapy with established therapeutics may further augment anti-cancer activity to overcome disease resistance.

Keywords: Cancer; ER stress; HRI; eIF2; translation.

Figure 1

Phosphorylation of eIF2α modulates protein synthesis. Phosphorylation of eIF2α on serine 51 may result from physiologic or pharmacologic activation of eIF2α kinases. There are four well-described eIF2α kinases: PERK, PKR, HRI, and GCN2 (see text for full names) each activated by a diverse set of cellular stressors. Phosphorylation of eIF2α results in attenuated guanine nucleotide (GDP/GTP) exchange activity as a result of inhibitory effects on the guanine nucleotide exchange factor (eIF2B). As a result, less eIF2-GTP-met-tRNAi ternary complex (TC) is able to be formed. Since ternary complexes are required for translation initiation, the end result is a general repression of protein synthesis. mRNAs with long or structured 5′ untranslated regions (UTRs), including many oncogenic mRNAs (e.g. growth factors, transcription factors) may be especially vulnerable to reduced TC abundance (weak 5′UTRs), compared to housekeeping mRNAs with more efficient 5′UTR sequences (strong 5′UTRs). 40S = 40S small ribosomal subunit.

Figure 2

eIF2α phosphorylation results in translational de-repression of select mRNAs. When eIF2α is in a non-phosphorylated state, as is seen during robust translational periods, there is abundant ternary complex (TC) availability for protein synthesis. For specific mRNAs with multiple upstream open reading frames (uORFs), ribosomal occupancy of inhibitory uORFs upstream of the start codon (main ORF) can lead to low levels of protein expression. In the setting of phosphorylated eIF2α, reduced availability of ternary complexes can lead to ribosomal bypass of inhibitory uORFs leading to translational de-repression and increased protein expression of select mRNAS. Notable examples of mRNAs that are regulated in this manner include activating transcription factor 4 (ATF4) and BRCA1. A simplified schematic is demonstrated for illustrative purposes. 60S = large ribosomal subunit. 40S = small ribosomal subunit. 80S = joined 80S ribosome.

Figure 3

Potential feedback loops and cross-talk following eIF2α phosphorylation. Activation of eIF2α phosphorylation by upstream kinases results in up-regulation of ATF4 and CHOP. Potential feedback loops that could attenuate eIF2α phosphorylation have been described, most notably through GADD34 and PP1c. In addition, activation of eIF2α kinases can be associated with up-regulation of PKB and mTOR signaling, as well as promotion of alternative translation initiation mechanisms such as those that utilize eIF2A. Dashed arrows are used to imply potential avenues of resistance, since feedback loops and cross-talk mechanisms may depend on the type of stress and cell system involved. Pharmacologic agents targeting upstream or downstream aspects of eIF2 signaling are annotated in italics. PP1c = protein phosphatase 1; GADD34 = protein phosphatase 1 regulatory subunit 15A; ATF4 = activating transcription factor 4; CHOP = DNA damage inducible transcript 3; eIF2 = eukaryotic translation initiation factor; PKB = protein kinase B; mTOR = mechanistic target of rapamycin; PERK/PKR/HRI/GCN2: See text for full names.