Abstract
Translation is a highly regulated process that is perturbed in human cancers, often through activation of the PI3K/mTOR pathway which impacts directly on the ribosome recruitment phase of translation initiation. While significant research has focused on “drugging” components of the PI3K/mTOR network, efforts have also been directed towards inhibiting eukaryotic initiation factor (eIF) 4F-dependent translation. Small molecule inhibitors of this complex have been identified, characterized, and used to validate the rationale of targeting this step to curtail tumor cell growth and modulate chemotherapy response. One such class of compounds are the rocaglates, secondary metabolites from the plant genus Aglaia, which target the RNA helicase subunit of eIF4F, eIF4A. Here we explore the ability of synthetic derivatives of aglaiastatins and an aglaroxin derivative to target the translation process in vitro and in vivo and find the synthetic derivative oxo-aglaiastatin to possess such activity. Oxo-aglaiastatin inhibited translation in vitro and in vivo and synergized with doxorubicin, ABT-199 (a Bcl-2 antagonist), and dexamethasone when tested on hematological cancer cells. The biological activity of oxo-aglaiastatin was shown to be a consequence of inhibiting eIF4A1 activity.
Highlights
Translation initiation in eukaryotes is a highly regulated process
We undertook a comparative assessment of the synthetic, racemic aglaiastatin derivative (CMLD010582), the synthetic derivative (+)-oxo-aglaiastatin (CMLD011580), and (−)-aglaroxin C (CMLD010833) to the two active rocaglates, (−)-CR-1-31-b and (−)-RocA (Fig. 1a)
This reporter encodes for firefly luciferase (FLuc) which reports on cap-dependent protein synthesis and renilla luciferase (RLuc) which is driven by the hepatitis C viral (HCV) internal ribosome entry site (IRES) and recruits ribosomes in an eIF4F-independent manner
Summary
Translation initiation in eukaryotes is a highly regulated process. A critical control point involves eukaryotic initiation factor (eIF) 4F, a complex that recruits the 40 S ribosome (and associated factors) to mRNA 5′ ends1,2. eIF4F is a heterotrimeric complex that binds the mRNA cap structure via its eIF4E subunit and utilizes its eIF4A helicase subunit to unwind local mRNA secondary structure in preparation for ribosome binding. eIF4F assembly falls under the governance of the PI3K/mTOR pathway, a signalling cascade usurped in the majority of human cancers - making it an attractive target for therapeutic development. Among the small molecules found to inhibit eIF4F activity, rocaglates have shown impressive potency and exert their effects through the selective inhibition of eIF4A4,5. They increase the binding of eIF4A to polypurine-enriched RNA sequences and cause depletion of eIF4A from the eIF4F complex[6,7,8]. Rocaglates are exclusive products of plants from the Aglaia (Meliaceae) genus These plants produce several cyclopenta[b]benzofuran-containing metabolites, among which rocaglamide (Roc) A (Fig. 1a) was the first isolated active compound and shown to exhibit anti-leukemic activity in mice[14]. We document the inhibitory effect of select synthetic aglaiastatin derivatives towards translation and compare their relative activity to previously studied rocaglates
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