The eIF2-alpha kinase HRI is a novel therapeutic target in multiple myeloma

Abstract

Dexamethasone (dex) induces apoptosis in multiple myeloma (MM) cells and is a frontline treatment for this disease. However resistance to dex remains a major challenge and novel treatment approaches are needed. We hypothesized that dex utilizes translational pathways to promote apoptosis in MM and that specific targeting of these pathways could overcome dex-resistance. Global unbiased profiling of mRNA translational profiles in MM cells treated with or without dex revealed that dex significantly repressed eIF2 signaling, an important pathway for regulating ternary complex formation and protein synthesis. We demonstrate that dex induces the phosphorylation of eIF2α resulting in the translational upregulation of ATF4, a known eIF2 regulated mRNA. Pharmacologic induction of eIF2α phosphorylation via activation of the heme-regulated eIF2α kinase (HRI) induced apoptosis in MM cell lines and in primary MM cells from patients with dex-resistant disease. In addition, co-culture with marrow stroma failed to protect MM cells from apoptosis induced by targeting the eIF2 pathway. Combination therapy with rapamycin, an mTOR inhibitor, and BTdCPU, an activator of HRI, demonstrated additive effects on apoptosis in dex-resistant cells. Thus, specific activation of the eIF2α kinase HRI is a novel therapeutic target in MM that can augment current treatment strategies.

HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells

“…Ours is the first study to identify HRI as the BZ-activated eIF2α kinase in pancreatic cancer models, and our data are consistent with the results of Fournier, et al ( 55 ) who implicated HRI in the BZ-induced formation of stress granules. Whereas other groups have begun activating HRI to sensitize multiple myeloma cells to therapy ( 56 ), our data provide a strong rationale for inhibiting HRI as a means of sensitizing pancreatic cancer cells to proteasome inhibitors. Notably, disruption of HRI signaling appears to be well-tolerated in vivo , as HRI -/- mice were found to be completely normal and fertile, with only mild hematologic abnormalities ( 10 ).…”

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

“…Though activation of HRI may have broad clinical applicability, some cancers such as MM and certain breast cancer subtypes may be particularly susceptible to reduced ternary complex formation caused by sustained eIF2α phosphorylation [32,33,42]. While HRI activators demonstrate single-agent activity in vivo , it will be especially helpful to elucidate how HRI activators pair with other therapeutics used clinically.…”

“…Experimentally, dominant negative PKR mutants, or eIF2α mutants that cannot be phosphorylated on serine 51, have been found to induce malignant transformation in NIH 3T3 cells [35]. In many cancers, eIF2α expression is increased when compared to normal tissue [32,36,37] and likely reflects the heightened translational demand in tumor cells. In some early-stage cancers, an increase in eIF2α kinase activity is observed and is associated with improved survival [38].…”

“…In this study, BTdCPU treatment lead to the rapid phosphorylation of eIF2α, expression of CHOP, and induction of apoptosis in both dexamethasone-sensitive and -resistant cells [32]. Proteasome inhibitors, which have potent clinical activity in MM, also induce eIF2α phosphorylation and expression of CHOP in MM cells [53,58].…”

“…Thus, while the induction of eIF2α phosphorylation via HRI is a viable anticancer strategy, the inhibition of eIF2α phosphorylation to augment effectiveness of PI3K-Akt blockade has also been proposed as a potential therapeutic combination [65]. Whether HRI activation results in similar cross talk is less clear, though in one study inhibition of mTOR augmented anticancer efficacy in combination with HRI activation in vitro [32]. The upregulation of ATF4 via eIF2α phosphorylation may itself serve to attenuate mTOR activity through the induction of mTOR repressors including Sestrin2 and REDD1 [66–68].…”