Heme-regulated inhibitor: an overlooked eIF2α kinase in cancer investigations

Heme-regulated inhibitor (HRI) kinase is a serine-threonine kinase, controlling the initiation of protein synthesis via phosphorylating alpha subunit of eIF2 on serine 51 residue, mainly in response to heme deprivation in erythroid cells. However, recent studies showed that HRI is also activated by several diverse signals, causing dysregulations in intracellular homeostatic mechanisms in non-erythroid cells. For instance, it was reported that the decrease in protein synthesis upon the 26S proteasomal inhibition by MG132 or bortezomib is mediated by increased eIF2 alpha phosphorylation in an HRI-dependent manner in mouse embryonic fibroblast cells. The increase in eIF2 alpha phosphorylation level through the activation of HRI upon 26S proteasomal inhibition is believed to protect cells against the buildup of misfolded and ubiquitinated proteins, having the potential to trigger the apoptotic response. In contrast, prolonged and sustained HRI-mediated eIF2 alpha phosphorylation can induce cell death, which may involve ATF4 and CHOP expression. Altogether, these studies suggest that HRI-mediated eIF2 alpha phosphorylation may be cytoprotective or cytotoxic depending on the cells, type, and duration of pharmacological agents used. It is thus hypothesized that both HRI activators, inducing eIF2 alpha phosphorylation or HRI inhibitors causing disturbances in eIF2 alpha phosphorylation, may be effective as novel strategies in cancer treatment if the balance in eIF2 alpha phosphorylation is shifted in favor of autophagic or apoptotic response in cancer cells. It is here aimed to review the role of HRI in various biological mechanisms as well as the therapeutic potentials of recently developed HRI activators and inhibitors, targeting eIF2 alpha phosphorylation in cancer cells.