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

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.