Poster Presentation 25th Lorne Cancer Conference 2013

Translation inhibitors induce cell death by multiple mechanisms and Mcl-1 reduction is only a minor contributor (#252)

Lisa M Lindqvist 1 , Ingela Vikström 1 , Jennifer M Chambers 2 , Kate McArthur 1 , Mary Ann Anderson 1 , Katya J Henley 1 , Lina Happo 1 , Leonie Cluse 3 , Ricky W Johnstone 3 , Andrew W Roberts 1 , Benjamin T Kile 1 , Ben A Croker 1 , Christopher J Burns 1 , Mark A Rizzacasa 2 , Andreas Strasser 1 , David CS Huang 1
  1. Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  2. School of Chemistry, The Bio21 Institute, The University of Melbourne, Parkville, Victoria, Australia
  3. Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
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) has recently been approved by the FDA for chronic myeloid leukemia, while 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. 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 play 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 also warn of potential toxicity since these translation inhibitors are cytotoxic to many differentiated non-cycling cells.