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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1717-1723.
Prepublished online as a Blood First Edition Paper on October 14, 2004; DOI 10.1182/blood-2004-03-0849.
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NEOPLASIA
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, and
Martin Sattler
From the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; and the Department of Medicine, University of Chicago, Pritzker School of Medicine, IL.
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 overactive 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. (Blood. 2005; 105:1717-1723)
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