title: 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.
authors.affiliation: Laboratory of Cytometry, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Kusio-Kobialka
authors.forename: Paulina
authors.initials: P
authors.lastname: Podszywalow-Bartnicka
authors.forename: Philippos
authors.initials: P
authors.lastname: Peidis
authors.forename: Eliza
authors.initials: E
authors.lastname: Glodkowska-Mrowka
authors.forename: Kamila
authors.initials: K
authors.lastname: Wolanin
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Leszak
authors.forename: Ilona
authors.initials: I
authors.lastname: Seferynska
authors.forename: Tomasz
authors.initials: T
authors.lastname: Stoklosa
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Piwocka
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000633:toxicity*; D001549:Benzamides; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D010879:Piperazines / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; D015852:Eukaryotic Initiation Factor-2; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D010879:Piperazines; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D019892:eIF-2 Kinase