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J. Biol. Chem., Vol. 283, Issue 4, 1992-2001, January 25, 2008

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Regulatory Effects of Mammalian Target of Rapamycin-mediated Signals in the Generation of Arsenic Trioxide Responses^*

Jessica K. Altman¹, Patrick Yoon¹, Efstratios Katsoulidis, Barbara Kroczynska, Antonella Sassano, Amanda J. Redig, Heather Glaser, Alison Jordan, Martin S. Tallman, Nissim Hay, and Leonidas C. Platanias²

From the Robert H. Lurie Comprehensive Cancer Center and Division of Hematology/Oncology, Northwestern University Medical School and Lakeside Veterans Affairs Medical Center, Chicago, Illinois 60611 and the Department of Molecular Genetics, University of Illinois, Chicago, Illinois 60607

Arsenic trioxide (As₂O₃) is a potent inducer of apoptosis of leukemic cells in vitro and in vivo, but the mechanisms that mediate such effects are not well understood. We provide evidence that the Akt kinase is phosphorylated/activated during treatment of leukemia cells with As₂O₃, to regulate downstream engagement of mammalian target of rapamycin (mTOR) and its effectors. Using cells with targeted disruption of both the Akt1 and Akt2 genes, we found that induction of arsenic trioxide-dependent apoptosis is strongly enhanced in the absence of these kinases, suggesting that Akt1/Akt2 are activated in a negative feedback regulatory manner, to control generation of As₂O₃ responses. Consistent with this, As₂O₃-dependent pro-apoptotic effects are enhanced in double knock-out cells for both isoforms of the p70 S6 kinase (S6k1/S6k2), a downstream effector of Akt and mTOR. On the other hand, As₂O₃-dependent induction of apoptosis is diminished in cells with targeted disruption of TSC2, a negative upstream effector of mTOR. In studies using primary hematopoietic progenitors from patients with acute myeloid leukemia, we found that pharmacological inhibition of mTOR enhances the suppressive effects of arsenic trioxide on leukemic progenitor colony formation. Moreover, short interfering RNA-mediated inhibition of expression of the negative downstream effector, translational repressor 4E-BP1, partially reverses the effects of As₂O₃. Altogether, these data provide evidence for a key regulatory role of the Akt/mTOR pathway in the generation of the effects of As₂O₃, and suggest that targeting this signaling cascade may provide a novel therapeutic approach to enhance the anti-leukemic properties of As₂O₃.

Received for publication, June 26, 2007 , and in revised form, November 28, 2007.

^* This work was supported by a Merit review grant by the Department of Veterans Affairs (to L. C. P.), National Institutes of Health Grants CA121192, CA77816, and CA100579 (to L. C. P.), and National Institutes of Health Training Grant T32 CA079447 (to J. K. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work and are joint first authors.

² To whom correspondence should be addressed: Robert H. Lurie Comprehensive Cancer Center, 303 East Superior St., Lurie 3-107, Chicago, IL 60611. Tel.: 312-503-4267; Fax: 312-908-1372; E-mail: l-platanias{at}northwestern.edu.

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