title: 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.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, 303 East Superior Street, Lurie 3-107, Chicago, IL 60611, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Yoon
authors.forename: Nick
authors.initials: N
authors.lastname: Giafis
authors.forename: Jessica
authors.initials: J
authors.lastname: Smith
authors.forename: Heather
authors.initials: H
authors.lastname: Mears
authors.forename: Efstratios
authors.initials: E
authors.lastname: Katsoulidis
authors.forename: Antonella
authors.initials: A
authors.lastname: Sassano
authors.forename: Jessica
authors.initials: J
authors.lastname: Altman
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Redig
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D011494:Protein Kinases; C546842:MTOR protein, human; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D000077237:Arsenic Trioxide