Translation inhibitors induce cell death by multiple mechanisms and Mcl-1 reduction is only a minor contributor

LM Lindqvist, I Vikstrom, JM Chambers, K McArthur, M Ann Anderson, KJ Henley, L Happo, L Cluse, RW Johnstone, AW Roberts, BT Kile, BA Croker, CJ Burns, MA Rizzacasa, A Strasser, DCS Huang

Research output: Contribution to journalArticleResearchpeer-review

29 Citations (Scopus)

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.

Original languageEnglish
Article numbere409
Number of pages9
JournalCell Death and Disease
Volume3
Issue number10
DOIs
Publication statusPublished - Oct 2012
Externally publishedYes

Keywords

  • Apoptosis
  • Homoharringtonine
  • Mcl-1
  • Protein synthesis
  • Silvestrol

Cite this

Lindqvist, LM., Vikstrom, I., Chambers, JM., McArthur, K., Anderson, M. A., Henley, KJ., ... Huang, DCS. (2012). Translation inhibitors induce cell death by multiple mechanisms and Mcl-1 reduction is only a minor contributor. Cell Death and Disease, 3(10), [e409]. https://doi.org/10.1038/cddis.2012.149
Lindqvist, LM ; Vikstrom, I ; Chambers, JM ; McArthur, K ; Anderson, M Ann ; Henley, KJ ; Happo, L ; Cluse, L ; Johnstone, RW ; Roberts, AW ; Kile, BT ; Croker, BA ; Burns, CJ ; Rizzacasa, MA ; Strasser, A ; Huang, DCS. / Translation inhibitors induce cell death by multiple mechanisms and Mcl-1 reduction is only a minor contributor. In: Cell Death and Disease. 2012 ; Vol. 3, No. 10.
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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.",
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Lindqvist, LM, Vikstrom, I, Chambers, JM, McArthur, K, Anderson, MA, Henley, KJ, Happo, L, Cluse, L, Johnstone, RW, Roberts, AW, Kile, BT, Croker, BA, Burns, CJ, Rizzacasa, MA, Strasser, A & Huang, DCS 2012, 'Translation inhibitors induce cell death by multiple mechanisms and Mcl-1 reduction is only a minor contributor', Cell Death and Disease, vol. 3, no. 10, e409. https://doi.org/10.1038/cddis.2012.149

Translation inhibitors induce cell death by multiple mechanisms and Mcl-1 reduction is only a minor contributor. / Lindqvist, LM; Vikstrom, I; Chambers, JM; McArthur, K ; Anderson, M Ann; Henley, KJ; Happo, L ; Cluse, L; Johnstone, RW; Roberts, AW; Kile, BT; Croker, BA; Burns, CJ; Rizzacasa, MA; Strasser, A; Huang, DCS.

In: Cell Death and Disease, Vol. 3, No. 10, e409, 10.2012.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Vikstrom, I

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AU - Happo, L

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AU - Huang, DCS

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