Activation of the PI3K/mTOR pathway by BCR-ABL contributes to increased production of reactive oxygen species

Jeong H Kim, Stephanie C Chu, Jessica L Gramlich, Yuri B Pride, Emily Babendreier, Dharminder Chauhan, Ravi Salgia, Klaus Podar, James D Griffin, Martin Sattler

Research output: Journal article (peer-reviewed)Journal article

193 Citations (Scopus)

Abstract

BCR-ABL oncoprotein-expressing cells are associated with a relative increase of intracellular reactive oxygen species (ROS), which is thought to play a role in transformation. Elevated ROS levels in BCR-ABL-transformed cells were found to be blocked by the mitochondrial complex I inhibitor rotenone as well as the glucose transport inhibitor phloretin, suggesting that the source of increased ROS might be related to increased glucose metabolism. The glucose analog 2-deoxyglucose (2-DOG) reduced ROS to levels found in non-BCR-ABL-transformed cells and inhibited cell growth alone or in cooperation with imatinib mesylate (Gleevec). A mutant of BCR-ABL that is defective in transformation of myeloid cells, Tyr177Phe, was also found to be defective in raising intracellular ROS levels. Glucose metabolism in BCR-ABL-transformed cells is likely to be mediated by activation of the phosphatidylinositol- 3′-kinase (PI3K) pathway, which is regulated through this site. Inhibition of PI3K or mTOR led to a significant decrease in ROS levels. Overall, our results suggest that elevated levels of ROS in BCR-ABL-transformed cells are secondary to a transformation-associated increase in glucose metabolism and an ovoractive mitochondrial electron transport chain and is specifically regulated by PI3K. Finally, these results hint at novel targets for drug development that may aid traditional therapy.

Original languageEnglish
Pages (from-to)1717-1723
Number of pages7
JournalBlood
Volume105
Issue number4
DOIs
Publication statusPublished - 15 Feb 2005
Externally publishedYes

Keywords

  • Benzamides
  • Cell Line
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic/metabolism
  • Deoxyglucose/pharmacology
  • Enzyme Activation
  • Fusion Proteins, bcr-abl/physiology
  • Humans
  • Imatinib Mesylate
  • Jurkat Cells
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology
  • Monosaccharide Transport Proteins/antagonists & inhibitors
  • Phloretin/pharmacology
  • Phosphatidylinositol 3-Kinases/metabolism
  • Piperazines/pharmacology
  • Protein Kinases/metabolism
  • Pyrimidines/pharmacology
  • Reactive Oxygen Species/metabolism
  • Signal Transduction/physiology
  • TOR Serine-Threonine Kinases
  • Tyrosine/genetics
  • Up-Regulation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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