The PERK-eIF2α phosphorylation arm is a pro-survival pathway of BCR-ABL signaling and confers resistance to imatinib treatment in chronic myeloid leukemia cells

Abstract

Activation of adaptive mechanisms plays a crucial role in cancer progression and drug resistance by allowing cell survival under stressful conditions. Therefore, inhibition of the adaptive response is considered as a prospective therapeutic strategy. The PERK-eIF2α phosphorylation pathway is an important arm of the unfolded protein response (UPR), which is induced under conditions of endoplasmic reticulum (ER) stress. Our previous work showed that ER stress is induced in chronic myeloid leukemia (CML) cells. Herein, we demonstrate that the PERK-eIF2α phosphorylation pathway is upregulated in CML cell lines and CD34+ cells from CML patients and is associated with CML progression and imatinib resistance. We also show that induction of apoptosis by imatinib results in the downregulation of the PERK-eIF2α phosphorylation arm. Furthermore, we demonstrate that inactivation of the PERK-eIF2α phosphorylation arm decreases the clonogenic and proliferative capacities of CML cells and sensitizes them to death by imatinib. These findings provide evidence for a pro-survival role of PERK-eIF2α phosphorylation arm that contributes to CML progression and development of imatinib resistance. Thus, the PERK-eIF2α phosphorylation arm may represent a suitable target for therapeutic intervention for CML disease.

Downregulation of BRCA1 protein in BCR-ABL1 leukemia cells depends on stress-triggered TIAR-mediated suppression of translation

“…10 Our previously shown data presented that TIAR, a known stress-responsive mRNA binding protein, binds to BRCA1 mRNA (Fig. 5) and is localized in the stress granules in CML cells (Fig.…”

“…9 In accordance to translation control, we showed that expression of BCR-ABL1 results in endoplasmic reticulum (ER) stress which leads to activation of unfolded protein response (UPR) and to phosphorylation of translation initiation factor 2 a subunit (eIF2a). 10 We found that this signaling cascade plays an essential role in imatinib resistance observed in CML cells. 10 Phosphorylation of eIF2a triggers TIA proteins action (TIA1/ TIAR), what briefly leads to rearrangement of cellular mRNA translation profile, thus protein synthesis profile in response to the cellular demand.…”

“…10 We found that this signaling cascade plays an essential role in imatinib resistance observed in CML cells. 10 Phosphorylation of eIF2a triggers TIA proteins action (TIA1/ TIAR), what briefly leads to rearrangement of cellular mRNA translation profile, thus protein synthesis profile in response to the cellular demand. 11,12 Here we report that BCR-ABL1 increased the half-life of BRCA1 mRNA, but repressed its translation.…”

“…11 As we previously shown that expression of BCR-ABL1 leads to activation of the eIF2a-dependent signaling, 10 the possible involvement of TIAR in the regulation of BRCA1 mRNA processing in CML cannot be excluded. Both, TIAR and HuR proteins can selectively target mRNAs by binding to specific AU-rich elements (AREs) located at the 3'UTR end of the target mRNAs and often cooperate in complex.…”

“…Previously we also reported that cells with BCR-ABL1 activate adaptive cytoprotective ER stress response connected with activation of the eIF2a-dependent signaling. 10 Thus, we wanted to verify whether these cells are prone to formation of stress granules containing TIAR and/or TIARHuR complexes. Cell were double immunostained for HuR and TIAR, and the nucleus was visualized with DAPI ( Fig.…”