Differential regulation of the p70 S6 kinase pathway by interferon alpha (IFNalpha) and imatinib mesylate (STI571) in chronic myelogenous leukemia cells.
The precise mechanisms by which imatinib mesylate (STI571) and interferon alpha (IFNalpha) 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 IFNalpha 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, IFNalpha 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.
Parmar
Simrit
S
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School, Lakeside Veterans Administration Medical Center, Section of Hematology-Oncology, University of Chicago, IL, USA.
Smith
Jessica
J
Sassano
Antonella
A
Uddin
Shahab
S
Katsoulidis
Efstratios
E
Majchrzak
Beata
B
Kambhampati
Suman
S
Eklund
Elizabeth A
EA
Tallman
Martin S
MS
Fish
Eleanor N
EN
Platanias
Leonidas C
LC
D020121:5' Untranslated Regions; D000730:Androstadienes / Q000494:pharmacology; D001549:Benzamides; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D016898:Interferon-alpha / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013234:Stem Cells; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D000077191:Wortmannin
D020121:5' Untranslated Regions; D000730:Androstadienes; D001549:Benzamides; D039561:Eukaryotic Initiation Factor-4E; D000068877:Imatinib Mesylate; D016898:Interferon-alpha; D019869:Phosphatidylinositol 3-Kinases; D010879:Piperazines; D011494:Protein Kinases; D011743:Pyrimidines; D012333:RNA, Messenger; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000077191:Wortmannin; C546842:MTOR protein, human