TY - JOUR
T1 - Differential regulation of the p70 S6 kinase pathway by interferon α (IFNα) and imatinib mesylate (STI571) in chronic myelogenous leukemia cells
AU - Parmar, Simrit
AU - Smith, Jessica
AU - Sassano, Antonella
AU - Uddin, Shahab
AU - Katsoulidis, Efstratios
AU - Majchrzak, Beata
AU - Kambhampati, Suman
AU - Eklund, Elizabeth A.
AU - Tallman, Martin S.
AU - Fish, Eleanor N.
AU - Platanias, Leonidas C.
PY - 2005/10
Y1 - 2005/10
N2 - The precise mechanisms by which imatinib mesylate (STI571) and interferon α (IFNα) exhibit antileukemic effects are not known. We examined the effects of IFNs or imatinib mesylate on signaling pathways regulating initiation of mRNA translation in BCR-ABL-expressing cells. Treatment of IFN-sensitive KT-1 cells with IFNα resulted in phosphorylation/activation of mammalian target of rapamycin (mTOR) and downstream activation of p70 S6 kinase. The IFN-activated p70 S6 kinase was found to regulate phosphorylation of S6 ribosomal protein, which regulates translation of mRNAs with oligopyrimidine tracts in the 5′-untranslated region. In addition, IFNα treatment resulted in an mTOR- and/or phosphatidyl-inositol 3′(PI 3′) kinase-dependent phosphorylation of 4E-BP1 repressor of mRNA translation on sites that are required for its deactivation and dissociation from the eukaryotic initiation factor-4E (eIF4E) complex. In contrast to the effects of IFNs, imatinib mesylate suppressed p70 S6 kinase activity, consistent with inhibition of BCR-ABL-mediated activation of the mTOR/p70 S6 kinase pathway. Moreover, the mTOR inhibitor rapamycin enhanced the suppressive effects of imatinib mesylate on primary leukemic granulocyte macrophage-colony-forming unit (CFU-GM) progenitors from patients with chronic myelogenous leukemia (CML). Taken altogether, our data demonstrate that IFNs and imatinib mesylate differentially regulate PI 3′ kinase/mTOR-dependent signaling cascades in BCR-ABL-transformed cells, consistent with distinct effects of these agents on pathways regulating mRNA translation. They also support the concept that combined use of imatinib mesylate with mTOR inhibitors may be an appropriate future therapeutic strategy for the treatment of CML.
AB - The precise mechanisms by which imatinib mesylate (STI571) and interferon α (IFNα) exhibit antileukemic effects are not known. We examined the effects of IFNs or imatinib mesylate on signaling pathways regulating initiation of mRNA translation in BCR-ABL-expressing cells. Treatment of IFN-sensitive KT-1 cells with IFNα resulted in phosphorylation/activation of mammalian target of rapamycin (mTOR) and downstream activation of p70 S6 kinase. The IFN-activated p70 S6 kinase was found to regulate phosphorylation of S6 ribosomal protein, which regulates translation of mRNAs with oligopyrimidine tracts in the 5′-untranslated region. In addition, IFNα treatment resulted in an mTOR- and/or phosphatidyl-inositol 3′(PI 3′) kinase-dependent phosphorylation of 4E-BP1 repressor of mRNA translation on sites that are required for its deactivation and dissociation from the eukaryotic initiation factor-4E (eIF4E) complex. In contrast to the effects of IFNs, imatinib mesylate suppressed p70 S6 kinase activity, consistent with inhibition of BCR-ABL-mediated activation of the mTOR/p70 S6 kinase pathway. Moreover, the mTOR inhibitor rapamycin enhanced the suppressive effects of imatinib mesylate on primary leukemic granulocyte macrophage-colony-forming unit (CFU-GM) progenitors from patients with chronic myelogenous leukemia (CML). Taken altogether, our data demonstrate that IFNs and imatinib mesylate differentially regulate PI 3′ kinase/mTOR-dependent signaling cascades in BCR-ABL-transformed cells, consistent with distinct effects of these agents on pathways regulating mRNA translation. They also support the concept that combined use of imatinib mesylate with mTOR inhibitors may be an appropriate future therapeutic strategy for the treatment of CML.
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U2 - 10.1182/blood-2004-10-4003
DO - 10.1182/blood-2004-10-4003
M3 - Article
C2 - 15790787
AN - SCOPUS:27144554961
SN - 0006-4971
VL - 106
SP - 2436
EP - 2443
JO - Blood
JF - Blood
IS - 7
ER -