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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. This Article Full Text (PDF) All Versions of this Article: 2004-03-0849v1 105/4/1717    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kim, J. H Articles by Sattler, M. Search for Related Content PubMed PubMed Citation Articles by Kim, J. H Articles by Sattler, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 5, 2004 Accepted October 6, 2004 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* Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Department of Medicine, University of Chicago, Pritzker School of Medicine, Chicago, IL, USA Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; * Corresponding author; email: martin_sattler{at}dfci.harvard.edu. 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 over-active 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. S. Fernandes, M. M. Reddy, J. R. Gonneville, S. C. DeRoo, K. Podar, J. D. Griffin, D. M. Weinstock, and M. Sattler BCR-ABL promotes the frequency of mutagenic single-strand annealing DNA repair Blood, August 27, 2009; 114(9): 1813 - 1819. [Abstract] [Full Text] [PDF] D. J. McCrann, A. Eliades, M. Makitalo, K. Matsuno, and K. 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