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Research Articles: Therapeutics, Targets, and Development

Activation of mammalian target of rapamycin and the p70 S6 kinase by arsenic trioxide in BCR-ABL–expressing cells

Robert H. Lurie Comprehensive Cancer Center and Division of Hematology/Oncology, Northwestern University Medical School and Lakeside VA Medical Center, Chicago, Illinois

Requests for reprints: Leonidas C. Platanias, Robert H. Lurie Comprehensive Cancer Center, 303 East Superior Street, Lurie 3-107, Chicago, IL 60611. Phone: 312-503-4267; Fax: 312-908-1372. E-mail: l-platanias{at}northwestern.edu

Abstract

Arsenic trioxide (As₂O₃) exhibits important antitumor activities in vitro and in vivo, but the precise mechanisms by which it induces its effects are not known. We provide evidence that during treatment of BCR-ABL–expressing cells with As₂O₃, there is activation of a cellular pathway involving the p70 S6 kinase (p70S6K). Our data show that p70S6K is rapidly phosphorylated on Thr⁴²¹ and Ser⁴²⁴ and is activated in an As₂O₃-inducible manner. The mammalian target of rapamycin (mTOR) is also phosphorylated/activated in an As₂O₃-inducible manner, and its activity is required for downstream engagement of p70S6K. p70S6K subsequently phosphorylates the S6 ribosomal protein on Ser²³⁵/Ser²³⁶ and Ser²⁴⁰/Ser²⁴⁴ to promote initiation of mRNA translation. Treatment of chronic myelogenous leukemia–derived cell lines with As₂O₃ also results in phosphorylation of the 4E-BP1 repressor of mRNA translation on Thr³⁷/Thr⁴⁶ and Thr⁷⁰, sites required for its deactivation and its dissociation from the eukaryotic initiation factor 4E complex to allow cap-dependent mRNA translation. In studies to determine the functional relevance of this pathway, we found that inhibition of mTOR and downstream cascades enhances induction of apoptosis by As₂O₃. Consistent with this, the mTOR inhibitor rapamycin strongly potentiated As₂O₃-mediated suppression of primitive leukemic progenitors from the bone marrow of chronic myelogenous leukemia patients. Altogether, our data show that the mTOR/p70S6K pathway is activated in a negative feedback regulatory manner in response to As₂O₃ in BCR-ABL–transformed cells and plays a key regulatory role in the induction of anti-leukemic responses. [Mol Cancer Ther 2006;5(11):2815–23]

Grant support: Department of Veterans Affairs (L.C. Platanias), NIH grants CA94079 and CA77816 (L.C. Platanias), and NIH/National Cancer Institute training grant T32 CA09560 (P. Yoon).

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.

Received 5/ 9/06; revised 8/24/06; accepted 9/11/06.

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