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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
- Source :
- Cell Cycle. 11:4069-4078
- Publication Year :
- 2012
- Publisher :
- Informa UK Limited, 2012.
-
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.
- Subjects :
- endocrine system
Myeloid leukemia
Imatinib
Cell Biology
Biology
medicine.disease
Leukemia
Imatinib mesylate
Downregulation and upregulation
hemic and lymphatic diseases
medicine
Cancer research
Unfolded protein response
Phosphorylation
neoplasms
Molecular Biology
Developmental Biology
medicine.drug
K562 cells
Subjects
Details
- ISSN :
- 15514005 and 15384101
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Cell Cycle
- Accession number :
- edsair.doi...........d48c1ea8c3459371ea4f9d1e45775363