Please use this identifier to cite or link to this item: https://doi.org/10.1128/MCB.00477-08
Title: Inhibition of polysome assembly enhances imatinib activity against chronic myelogenous leukemia and overcomes imatinib resistance
Authors: Zhang, M.
Fu, W.
Prabhu, S.
Moore, J.C.
Ko, J.
Kim, J.W.
Druker, B.J.
Trapp, V.
Fruehauf, J.
Gram, H.
Fan, H.Y.
Ong, S.T. 
Issue Date: Oct-2008
Citation: Zhang, M., Fu, W., Prabhu, S., Moore, J.C., Ko, J., Kim, J.W., Druker, B.J., Trapp, V., Fruehauf, J., Gram, H., Fan, H.Y., Ong, S.T. (2008-10). Inhibition of polysome assembly enhances imatinib activity against chronic myelogenous leukemia and overcomes imatinib resistance. Molecular and Cellular Biology 28 (20) : 6496-6509. ScholarBank@NUS Repository. https://doi.org/10.1128/MCB.00477-08
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. Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Source Title: Molecular and Cellular Biology
URI: http://scholarbank.nus.edu.sg/handle/10635/132485
ISSN: 02707306
DOI: 10.1128/MCB.00477-08
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
There are no files associated with this item.

SCOPUSTM   
Citations

42
checked on Sep 13, 2018

WEB OF SCIENCETM
Citations

40
checked on Sep 4, 2018

Page view(s)

25
checked on Sep 6, 2018

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.