title: Inhibition of polysome assembly enhances imatinib activity against chronic myelogenous leukemia and overcomes imatinib resistance.
abstract: Dysregulated mRNA translation is implicated in the pathogenesis of many human cancers including chronic myelogenous leukemia (CML). Because our prior work has specifically implicated translation initiation in CML, we tested compounds that could modulate translation initiation and polysomal mRNA assembly. Here, we evaluated the activity of one such compound, CGP57380, against CML cells and explored its mechanisms of action. First, using polysomal mRNA profiles, we found that imatinib and CGP57380 could independently, and cooperatively, impair polysomal mRNA loading. Imatinib and CGP57380 also synergistically inhibited the growth of Ba/F3-Bcr-Abl and K562 cells via impaired cell cycle entry and increased apoptosis. Mechanistically, CGP57380 inhibited efficient polysomal assembly via two processes. First, it enhanced imatinib-mediated inhibition of eukaryotic initiation factor 4F induction, and second, it independently impaired phosphorylation of ribosomal protein S6 on the preinitiation complex. We also identified multiple substrates of the mTOR, Rsk, and Mnk kinases as targets of CGP57380. Finally, we found a novel negative-feedback loop to the mitogen-activated protein kinase/Mnk pathway that is triggered by CGP57380 and demonstrated that an interruption of the loop further increased the activity of the combination against imatinib-sensitive and -resistant CML cells. Together, this work supports the inhibition of translation initiation as a therapeutic strategy for treating cancers fueled by dysregulated translation.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California at Irvine, Irvine, California 92697, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Wuxia
authors.initials: W
authors.lastname: Fu
authors.forename: Sharmila
authors.initials: S
authors.lastname: Prabhu
authors.forename: James C
authors.initials: JC
authors.lastname: Moore
authors.forename: Je
authors.initials: J
authors.lastname: Ko
authors.forename: Jung Woo
authors.initials: JW
authors.lastname: Kim
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Valerie
authors.initials: V
authors.lastname: Trapp
authors.forename: John
authors.initials: J
authors.lastname: Fruehauf
authors.forename: Hermann
authors.initials: H
authors.lastname: Gram
authors.forename: Hung Y
authors.initials: HY
authors.lastname: Fan
authors.forename: S Tiong
authors.initials: ST
authors.lastname: Ong
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011132:Polyribosomes / Q000187:drug effects* / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D012315:RNA Caps / Q000378:metabolism; D034443:RNA Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases
chemical_list: D000814:Aniline Compounds; D001549:Benzamides; C466997:CGP 57380; D039562:Eukaryotic Initiation Factor-4F; D010879:Piperazines; D011687:Purines; D011743:Pyrimidines; D012315:RNA Caps; D012333:RNA, Messenger; D038601:Ribosomal Protein S6; D000068877:Imatinib Mesylate; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases