Altering Chemosensitivity by Modulating Translation Elongation

Abstract

BackgroundThe process of translation occurs at a nexus point downstream of a number of signal pathways and developmental processes. Modeling activation of the PTEN/AKT/mTOR pathway in the Eμ-Myc mouse is a valuable tool to study tumor genotype/chemosensitivity relationships in vivo. In this model, blocking translation initiation with silvestrol, an inhibitor of the ribosome recruitment step has been showed to modulate the sensitivity of the tumors to the effect of standard chemotherapy. However, inhibitors of translation elongation have been tested as potential anti-cancer therapeutic agents in vitro, but have not been extensively tested in genetically well-defined mouse tumor models or for potential synergy with standard of care agents.Methodology/Principal FindingsHere, we chose four structurally different chemical inhibitors of translation elongation: homoharringtonine, bruceantin, didemnin B and cycloheximide, and tested their ability to alter the chemoresistance of Eμ-myc lymphomas harbouring lesions in Pten, Tsc2, Bcl-2, or eIF4E. We show that in some genetic settings, translation elongation inhibitors are able to synergize with doxorubicin by reinstating an apoptotic program in tumor cells. We attribute this effect to a reduction in levels of pro-oncogenic or pro-survival proteins having short half-lives, like Mcl-1, cyclin D1 or c-Myc. Using lymphomas cells grown ex vivo we reproduced the synergy observed in mice between chemotherapy and elongation inhibition and show that this is reversed by blocking protein degradation with a proteasome inhibitor.Conclusion/SignificanceOur results indicate that depleting short-lived pro-survival factors by inhibiting their synthesis could achieve a therapeutic response in tumors harboring PTEN/AKT/mTOR pathway mutations.

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…163) As stated previously, the tumor suppressor TSC2 lies above mTORC1 in this pathway. One of the deregulated targets in the TSC2-(loss of heterozygosity)/Em-Myc lymphomas is Mcl-1 (ref.…”

“…Mcl-1 can counteract some of the pro-apoptotic events induced by c-Myc in the Em-Myc mice and result in lymphomas. 161,163,164 As mentioned before the Rheb GTPase is an activator of mTORC1. Rheb is highly expressed in some human lymphomas 31,[165][166][167] and other cancers.…”

“…However, the combination of c-Myc expression and Rheb prevented the induction of senescence induced by Rheb and the apoptosis induced by c-Myc, which may explain the increased incidence of lymphomas in the Rheb/Em-Myc mice than in Em-Myc mice. 161,163,164 This group has shown that the abilities of Ras, Akt and Rheb to activate cellular senescence are dependent, at least in part, on their ability to activate mTORC1. This effect may be owing to eIF4B activation as eIF4B also induces cellular senescence.…”

Inhibition of translation by cytotrienin A—a member of the ansamycin family

“…Higher translation rates also occur in human tumors and appear to be required to maintain their oncogenic state (Heys et al 1991;Wendel et al 2004). These latter two points may explain why some inhibitors of translation elongation show efficacy in preclinical cancer models as well as in the clinic (QuintasCardama et al 2009;Robert et al 2009). …”

Omacetaxine mepesuccinate prevents cytokine-dependent resistance to nilotinib in vitro: potential role of the common β-subunit c of cytokine receptors

“…Consistent with previous reports, OM depletes the cells of the protein of interest not only by prevention of synthesis, but also by induction of proteasomal degradation, as we show by demonstration of re-expression of cCRbc in the presence of the proteasome inhibitor MG-132 (Figure 6a). 32 Several points of convergence between cCRbc-and BCR-ABL-dependent signaling have been reported, which explains their overlapping pro-survival and proliferative activity in hematopoietic cells. 2 Transformation of factor-dependent cells by BCR-ABL leads to downregulation of cCRbc.…”