Report

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

Volume 11, Issue 21   November 1, 2012
Pages 4069 - 4078
http://dx.doi.org/10.4161/cc.22387
Keywords: BCR-ABL, CML, ER stress, PERK, eIF2α phosphorylation, imatinib
Authors: Monika Kusio-Kobialka, Paulina Podszywalow-Bartnicka, Philippos Peidis, Eliza Glodkowska-Mrowka, Kamila Wolanin, Grzegorz Leszak, Ilona Seferynska, Tomasz Stoklosa, Antonis E. Koromilas and Katarzyna Piwocka

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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.

Received: September 14, 2012; Accepted: September 28, 2012; Published Online: October 24, 2012

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