Open AccessInhibition of Polysome Assembly Enhances Imatinib Activity against Chronic Myelogenous Leukemia and Overcomes Imatinib Resistance
Author(s) -
Min Zhang,
Wuxia Fu,
Sharmila Prabhu,
James C. Moore,
Je Yeong Ko,
Jung Ho Kim,
Brian J. Druker,
Valerie Trapp,
John P. Fruehauf,
Hermann Gram,
Hung Fan,
S. Tiong Ong
Publication year - 2008
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.00477-08
Subject(s) - biology , chronic myelogenous leukemia , k562 cells , translation (biology) , eif4e , imatinib , polysome , cancer research , messenger rna , ribosomal s6 kinase , initiation factor , microbiology and biotechnology , imatinib mesylate , kinase , pi3k/akt/mtor pathway , leukemia , signal transduction , p70 s6 kinase 1 , ribosome , gene , immunology , biochemistry , rna , myeloid leukemia
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.