Could the eIF2α-Independent Translation Be the Achilles Heel of Cancer?

Abstract

Eukaryotic initiation factor eIF2 is a key component of the ternary complex whose role is to deliver initiator tRNA into the ribosome. A variety of stimuli, both physiologic and pathophysiologic activate eIF2 kinases that phosphorylate the α subunit of eIF2, preventing it from forming the ternary complex, thus attenuating cellular protein synthesis. Paradoxically, in cancer cells, the phosphorylation of eIF2α is associated with activation of survival pathways. This review explores the recently emerged novel mechanism of eIF2α-independent translation initiation. This mechanism, which appears to be shared by some RNA viruses and Internal Ribosome Entry Site-containing cellular mRNAs and utilizes auxiliary proteins, such as eIF5B, eIF2D, and MCT-1, is responsible for the selective translation of cancer-associated genes and could represent a weak point amenable to specific targeting for the treatment of cancer.

Keywords: IRES; apoptosis; eIF2α; oncogene; selective translation; stress.

Figure 1

eIF2α is a control nexus integrating diverse stimuli to regulate translation. The eukaryotic initiation factor 2 (eIF2) is required for the formation of the ternary complex [consisting of eIF2 (α, β, and γ subunits), Met-tRNA_i, and GTP] whose role is to deliver the initiator Met-tRNA_i to the P site of the 40S ribosomal subunit, enabling translation initiation. eIF2 exists in two distinct configurations – the GDP bound (inactive) and GTP bound (active), but only the GTP-bound form can bind Met-tRNA_i. In response to diverse stress stimuli, distinct protein kinases phosphorylate the α subunit of eIF2 at serine 51, ultimately locking eIF2 in an inactive eIF2 complex with eIF2B. As a result, availability of the ternary complex significantly declines ultimately resulting in the inhibition of translation globally. Selective translation of a subset of mRNAs with uORFs continues, however, allowing cells to express proteins required for adaptation to stress conditions.

Figure 2

eIF2α-independent translation in cancer. Cancer environment, such as hypoxia, growth factor and cytokine signaling, and various forms of stress, leads to enhanced phosphorylation or proteolytic degradation of eIF2α which causes attenuation of protein synthesis due to unavailability of the ternary complex (right). However, this allows Met-tRNA_i to form an alternative ternary complex with proteins like eIF5B, eIF2D, and DENR/MCT-1 (left). Alternative ternary complex supports translation of select mRNAs, including those regulating apoptosis and cell cycle progression, in an eIF2α-independent manner, ultimately providing the cancer cell with a survival advantage. Specific targeting of the eIF2α-independent translation mechanism therefore offers a possible therapeutic target to treat cancer.