Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/124968
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Type: Journal article
Title: Translation inhibitors induce cell death by multiple mechanisms and Mcl-1 reduction is only a minor contributor
Author: Lindqvist, L.
Vikström, I.
Chambers, J.
McArthur, K.
Ann Anderson, M.
Henley, K.
Happo, L.
Cluse, L.
Johnstone, R.
Roberts, A.
Kile, B.
Croker, B.
Burns, C.
Rizzacasa, M.
Strasser, A.
Huang, D.
Citation: Cell Death and Disease, 2012; 3(10):e409-1-e409-9
Publisher: Nature Publishing Group
Issue Date: 2012
ISSN: 2041-4889
2041-4889
Statement of
Responsibility: 
L. M Lindqvist, I Vikström, J M Chambers, K McArthur, M Ann Anderson ... B T Kile ... et al.
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.
Keywords: Protein synthesis; silvestrol; homoharringtonine; Mcl-1; apoptosis
Rights: 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/
RMID: 1000001883
DOI: 10.1038/cddis.2012.149
Grant ID: http://purl.org/au-research/grants/nhmrc/461219
http://purl.org/au-research/grants/nhmrc/461221
http://purl.org/au-research/grants/nhmrc/1016701
http://purl.org/au-research/grants/nhmrc/454569
http://purl.org/au-research/grants/nhmrc/637360
http://purl.org/au-research/grants/nhmrc/637367
http://purl.org/au-research/grants/nhmrc/637326
http://purl.org/au-research/grants/nhmrc/1028871
Appears in Collections:Environment Institute publications

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