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Molecular and Cellular Biology, October 2008, p. 6496-6509, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00477-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Inhibition of Polysome Assembly Enhances Imatinib Activity against Chronic Myelogenous Leukemia and Overcomes Imatinib Resistance{triangledown}

Min Zhang,1 Wuxia Fu,1 Sharmila Prabhu,1 James C. Moore,1 Je Ko,1 Jung Woo Kim,1,{dagger} Brian J. Druker,2 Valerie Trapp,1 John Fruehauf,1 Hermann Gram,3 Hung Y. Fan,1,4,5 and S. Tiong Ong1,5*

Division of Hematology/Oncology, Department of Medicine, University of California at Irvine, Irvine, California,1 Howard Hughes Medical Institute, Oregon Health and Science University Cancer Institute, Portland, Oregon 97239,2 Novartis Institutes for Biomedical Research, Basel, Switzerland,3 Department of Molecular Biology and Biochemistry, School of Biological Sciences,4 Cancer Research Institute, University of California at Irvine, Irvine, California 926975

Received 22 March 2008/ Returned for modification 2 May 2008/ Accepted 28 July 2008

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.

* Corresponding author. Present address: Duke-NUS Graduate Medical School, 2 Jalan Bukit Merah, Singapore 169547. Phone: 65 6516 7763. Fax: 65 6534 8632. E-mail: sintiong.ong{at}duke-nus.edu.sg

{triangledown} Published ahead of print on 11 August 2008.

{dagger} Present address: Paichai Bio-Diagnostic Fusion Technology Center, Dept. of Life Science and Technology, Pai Chai University, Daejeon, Republic of Korea 302-735.

Molecular and Cellular Biology, October 2008, p. 6496-6509, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00477-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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