Translation inhibitors induce cell death by multiple mechanisms and Mcl-1 reduction is only a minor contributor
Journal Title
CELL DEATH & DISEASE
Publication Type
Journal Article
Abstract
There is significant interest in treating cancers by blocking protein synthesis, to which hematological malignancies seem particularly sensitive. The translation elongation inhibitor homoharringtonine (Omacetaxine mepesuccinate) is undergoing clinical trials for chronic myeloid leukemia, whereas the translation initiation inhibitor silvestrol has shown promise in mouse models of cancer. Precisely how these compounds induce cell death is unclear, but reduction in Mcl-1, a labile pro-survival Bcl-2 family member, has been proposed to constitute the critical event. Moreover, the contribution of translation inhibitors to neutropenia and lymphopenia has not been precisely defined. Herein, we demonstrate that primary B cells and neutrophils are highly sensitive to translation inhibitors, which trigger the Bax/Bak-mediated apoptotic pathway. However, contrary to expectations, reduction of Mcl-1 did not significantly enhance cytotoxicity of these compounds, suggesting that it does not have a principal role and cautions that strong correlations do not always signify causality. On the other hand, the killing of T lymphocytes was less dependent on Bax and Bak, indicating that translation inhibitors can also induce cell death via alternative mechanisms. Indeed, loss of clonogenic survival proved to be independent of the Bax/Bak-mediated apoptosis altogether. Our findings warn of potential toxicity as these translation inhibitors are cytotoxic to many differentiated non-cycling cells. Cell Death and Disease (2012) 3, e409; doi:10.1038/cddis.2012.149; published online 11 October 2012
Publisher
NATURE PUBLISHING GROUP
Keywords
CHRONIC LYMPHOCYTIC-LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; PROTEIN-SYNTHESIS; THERAPEUTIC SUPPRESSION; INDUCED APOPTOSIS; TUMOR-FORMATION; BCL-2 PROTEINS; C-MYC; INITIATION; HOMOHARRINGTONINE
WEHI Research Division(s)
Chemical Biology; Cancer And Haematology; Inflammation; Immunology; Molecular Genetics Of Cancer; Cell Signalling And Cell Death
NHMRC Grants
NHMRC/461219 NHMRC/461221 NHMRC/1016701
Rights Notice
Copyright © 2012 Macmillan Publishers Limited This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/


Creation Date: 2012-10-01 12:00:00
Last Modified: 0001-01-01 12:00:00
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