Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model

Abstract

Disablement of cell death programs in cancer cells contributes to drug resistance and in some cases has been associated with altered translational control. As eukaryotic translation initiation factor 4E (eIF4E) cooperates with c-Myc during lymphomagenesis, induces drug resistance, and is a genetic modifier of the rapamycin response, we have investigated the effect of dysregulation of the ribosome recruitment phase of translation initiation on tumor progression and chemosensitivity. eIF4E is a subunit of eIF4F, a complex that stimulates ribosome recruitment during translation initiation by delivering the DEAD-box RNA helicase eIF4A to the 5′ end of mRNAs. eIF4A is thought to prepare a ribosome landing pad on mRNA templates for incoming 40S ribosomes (and associated factors). Using small molecule screening, we found that cyclopenta[b]benzofuran flavaglines, a class of natural products, modulate eIF4A activity and inhibit translation initiation. One member of this class of compounds, silvestrol, was able to enhance chemosensitivity in a mouse lymphoma model in which carcinogenesis is driven by phosphatase and tensin homolog (PTEN) inactivation or elevated eIF4E levels. These results establish that targeting translation initiation can restore drug sensitivity in vivo and provide an approach to modulating chemosensitivity.

mi RISC and the CCR 4– NOT complex silence mRNA targets independently of 43S ribosomal scanning

“…We further confirmed that translation of the TISU reporter was independent of scanning, and thus of eIF4A activity, using silvestrol, a compound that stimulates eIF4A1/2 RNA‐binding activity, reducing the pool of the protein available for translation (Bordeleau et al , 2008; Cencic et al , 2009). Silvestrol inhibited cap‐dependent translation of Renilla luciferase, but the translation driven by the TISU sequence was only marginally inhibited (Fig 4A) as expected (Elfakess et al , 2011).…”

Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F

“…As well, antisense RNA oligonucleotides directed to eIF4E (9), peptides directed to the eIF4E:eIF4G interaction site (10), or small molecule inhibition of the eIF4E:eIF4G interaction (11) suppress transformation and induce apoptosis in vitro, although the potential of these approaches has not been tested in vivo. Importantly, and more clinically relevant, antisense targeting of eIF4E (12) or small molecule inhibition of eIF4A helicase activity (13,14) show promising efficacy in blocking tumor growth in vivo in several preclinical cancer models. Herein, we explore the consequences of blocking eIF4E:eIF4G interaction in vivo on chemoresistance in a genetically defined preclinical lymphoma model.…”

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

“…Silvestrol and related compounds may be able to enhance chemosensitivity in cancers (for example, lymphomas), which grow in response to deregulated PTEN and downstream eIF4E. 162 …”