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

L M Lindqvist,A W Roberts,K Mcarthur,B T Kile,L Cluse,A Strasser,Dc S Huang,B A Croker,M Ann Anderson,L Happo,M A Rizzacasa,R W Johnstone,J M Chambers,C J Burns,I Vikström,K J Henley

doi:10.1038/cddis.2012.149

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.

Highlights

Helicase eIF4A and the cap-binding protein eIF4E, two members of the eIF4F complex.[1,2] eIF4E has transforming activity and cooperates with deregulated Myc expression in lymphomagenesis and mice deficient in the eIF4A inhibitor Pdcd[4] develop lymphoma.[3,4,5,6] Translation elongation factors are upregulated in a range of malignancies.[7]
Many human leukemia-derived cells are highly sensitive to inhibitors of protein synthesis
As cell lines derived from several hematopoietic malignancies have been reported to be sensitive to silvestrol and HHT,[14,15,17] we evaluated a panel of leukemias to determine if some cell types are more sensitive than others

Summary

Introduction

Helicase eIF4A and the cap-binding protein eIF4E, two members of the eIF4F complex.[1,2] eIF4E has transforming activity and cooperates with deregulated Myc expression in lymphomagenesis and mice deficient in the eIF4A inhibitor Pdcd[4] develop lymphoma.[3,4,5,6] Translation elongation factors are upregulated in a range of malignancies.[7] As rapidly cycling cells require increased translation rates, it was postulated that they might be more sensitive to inhibition of protein synthesis.[8,9]. Inhibitors of translation elongation, such as HHT, inhibit global protein synthesis, targeting the eIF4F complex has been proposed to be more selective, because the translation of certain mRNAs is thought to be dependent on eIF4F.18 These eIF4F-dependent mRNAs often have highly structured 50 untranslated regions and many of them encode proteins involved in controlling cellular proliferation, survival (e.g., Mcl-1) and/or oncogenesis.[19,20]

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Results

Conclusion