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

Abstract
Arsenic trioxide (As(2)O(3)) 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 As(2)O(3), there is activation of a cellular pathway involving the p70 S6 kinase (p70S6K). Our data show that p70S6K is rapidly phosphorylated on Thr(421) and Ser(424) and is activated in an As(2)O(3)-inducible manner. The mammalian target of rapamycin (mTOR) is also phosphorylated/activated in an As(2)O(3)-inducible manner, and its activity is required for downstream engagement of p70S6K. p70S6K subsequently phosphorylates the S6 ribosomal protein on Ser(235)/Ser(236) and Ser(240)/Ser(244) to promote initiation of mRNA translation. Treatment of chronic myelogenous leukemia-derived cell lines with As(2)O(3) also results in phosphorylation of the 4E-BP1 repressor of mRNA translation on Thr(37)/Thr(46) and Thr(70), 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 As(2)O(3). Consistent with this, the mTOR inhibitor rapamycin strongly potentiated As(2)O(3)-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 As(2)O(3) in BCR-ABL-transformed cells and plays a key regulatory role in the induction of anti-leukemic responses.
AuthorsPatrick Yoon, Nick Giafis, Jessica Smith, Heather Mears, Efstratios Katsoulidis, Antonella Sassano, Jessica Altman, Amanda J Redig, Martin S Tallman, Leonidas C Platanias
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 5 Issue 11 Pg. 2815-23 (Nov 2006) ISSN: 1535-7163 [Print] United States
PMID17121928 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Arsenicals
  • Oxides
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • Ribosomal Protein S6 Kinases, 70-kDa
  • arsenic trioxide
Topics
  • Antineoplastic Agents (pharmacology)
  • Arsenicals (pharmacology)
  • Dose-Response Relationship, Drug
  • Fusion Proteins, bcr-abl
  • Humans
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, metabolism)
  • Oxides (pharmacology)
  • Phosphorylation (drug effects)
  • Protein Kinases (metabolism)
  • Protein-Tyrosine Kinases (metabolism)
  • Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
  • Signal Transduction (drug effects)
  • TOR Serine-Threonine Kinases
  • Tumor Cells, Cultured

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