BCR-ABL tyrosine kinase inhibition induces metabolic vulnerability by preventing the integrated stress response in K562 cells

Yu Kato, Kazuhiro Kunimasa, Yoshikazu Sugimoto, Akihiro Tomida

Research output: Contribution to journalArticle

Abstract

The integrated stress response (ISR) is a cellular process that is characterized by activation of eukaryotic initiation factor (eIF)2α kinases and subsequent induction of activating transcription factor (ATF)4. The ISR plays an important role in protecting cells from tumor-related metabolic stresses, such as nutrient deprivation and perturbed proteostasis. Here, we showed that disruption of the ISR, together with increased cellular stress vulnerability, was produced by pharmacological inhibition of BCR-ABL, the oncogenic driver in chronic myeloid leukemia (CML). Treatment of CML-derived K562 cells with BCR-ABL tyrosine kinase inhibitors, including imatinib, dasatinib, nilotinib and ponatinib, prevented activation of eIF2α kinases, protein kinase-like endoplasmic reticulum kinase (PERK) and general control nonderepressible 2, and downstream ATF4 induction during metabolic stress. Prevention of ATF4 induction likely occurred as a result of the combinatorial suppression of the eIF2α kinase and phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathways. In addition, we found that pharmacological inhibition of PERK mimicked BCR-ABL inhibition to enhance apoptosis induction under stress conditions. These findings indicate that the ISR is under the control of BCR-ABL and may foster adaptation to tumorigenic stresses in CML cells.

Original languageEnglish
Pages (from-to)721-726
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume504
Issue number4
DOIs
Publication statusPublished - 2018 Oct 12

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Keywords

  • ATF4
  • BCR-ABL
  • GCN2
  • Integrated stress response
  • PERK

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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