Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Emerging Therapeutics Targeting mRNA Translation Abba Malina1, John R. Mills1, and Jerry Pelletier1,2 1Department of Biochemistry and McGill University, Montre´al, Que´bec H3G 1Y6, Canada 2Rosalind and Morris Goodman Cancer Center, McGill University, Montre´al, Que´bec H3G 1Y6, Canada Correspondence: [email protected] A defining feature of many cancers is deregulated translational control. Typically, this occurs at the level of recruitment of the 40S ribosomes to the 50-cap of cellular messenger RNAs (mRNAs), the rate-limiting step of protein synthesis, which is controlled by the heterotrimeric eukaryotic initiation complex eIF4F. Thus, eIF4F in particular, and translation initiation in general, represent an exploitable vulnerability and unique opportunity for therapeutic inter- vention in many transformed cells. In this article, we discuss the development, mode of action and biological activity of a number of small-molecule inhibitors that interrupt PI3K/mTOR signaling control of eIF4F assembly, as well as compounds that more directly block eIF4F activity. t would seem fitting to finish this collection potential of eukaryotic protein synthesis inhib- Iwith an article on the topic of “emerging ther- itors were limited to tools in basic research. This apeutics in mRNA translation” because much view has changed during the last 20 years of of our current thinking into the molecular biol- research. We now have a more profound under- ogy of this rich field owes a great debt to inhib- standing of the complex regulatory apparatus itors of protein synthesis. The experimental use that the eukaryotic cell uses to control messen- of antibiotics that block the ribosome at key ger RNA (mRNA) translation and, with the enzymatic steps has been instrumental in defin- emergence of several novel compounds that tar- ing general features of translation and identi- get steps other than elongation, a greater appre- fying paradigms of translational control. From ciation of the rewiring of translation factors that a therapeutic perspective, however, it has only occurs in human disease, and most notably, been those antibiotics that inhibit prokaryot- cancer (Silvera et al. 2010). This latter and ex- ic protein synthesis that have had any medical citing development forms the basis of this arti- success, contributing significantly to the treat- cle. For a more complete description of other ment of bacterial infectious disease (Chambers known protein synthesis inhibitors we refer the 2001a,b). It thus had seemed that the use and reader to Pelletier and Peltz (2007). Editors: John W.B. Hershey, Nahum Sonenberg, and Michael B. Mathews Additional Perspectives on Protein Synthesis and Translational Control available at www.cshperspectives.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved. Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a012377 1 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press A. Malina et al. TARGETING TRANSLATION INITIATION AS evaluation of these drugs in combination ther- AN ANTINEOPLASTIC APPROACH apies (Robert et al. 2009). Other elongation inhibitors have had less The earliest, most varied and most widely stud- clinical success when applied toward the treat- ied inhibitors of eukaryotic protein synthe- ment of cancer owing to unacceptable toxicities sis are those that target the elongation step orpoorpharmacologicalpropertieslimitingtheir of mRNA translation (Pestka 1977; Vazquez therapeutic window (Dumez et al. 2009). Not 1979). Most of them act either by impairing surprisingly, the current trend in the develop- peptidyl transferase function, impeding trans- ment of therapeutic agents that disrupt trans- location, or interfering with aminoacyl-tRNA lation has thus drifted away from inhibitors (transfer RNA) binding or accommodation. of elongation to those that target initiation, po- Despite their structural diversity and nuanced tentially shifting the pharmacological response specificities, most eukaryotic elongation in- from global protein synthesis to a more selec- hibitors have shown limited therapeutic value tive (and possibly more cancer cell-dependent) especially when compared to their prokaryot- translationally regulated effect. ic counterparts, most likely owing to nonspe- cific toxicity derived from blocking global eIF4F and Tumorigenesis protein synthesis in nontransformed cells at the doses tested. Even with these apparent lim- The eIF4F translation complex is currently at itations, there has been renewed interest in the forefront of the development of pharma- using translation elongation inhibitors as anti- cological agents that block initiation. Briefly, neoplastics. For example, homoharringtonine eIF4F is a heterotrimeric complex composed (omacetaxine mepesuccinate or HHT), a tree- of eIF4E, the m7GpppN cap-binding protein derived alkaloid from the conifer Cephalotaxus that anchors the complex to the 50-end of the harringtonia, has shown promise in several clin- mRNA; eIF4A, an RNA DEAD box helicase ical trials for myelodysplastic syndrome and that is thought to unwind RNA secondary struc- in phase II clinical trials in patients with glee- ture surrounding the cap and increase the ef- vec-resistant chronic myelogenous leukemia ficiency of ribosome binding; and eIF4G, a large and in acute myeloid leukemia (AML) (Kan- scaffolding protein that bridges eIF4F to the tarjian et al. 2001; Kim et al. 2011). HHT is 43S ribosomal complex (see Lorsch et al. 2012). thought to inhibit peptide chain elongation by Given eIF4E’s limited abundance, the recruit- binding the A site of the ribosome, blocking ment of the 43S ribosomal complex to the aminoacyl-tRNA binding, and halting peptide mRNA by eIF4F is thought to be rate limiting chain elongation (Gurel et al. 2009). Recent ex- for translation initiation (Duncan et al. 1987). periments have provided some understanding The interaction of eIF4F with the cap structure of the possible mechanism of HHT’s mode of is affected by mRNA proximal secondary struc- action. On treatment of leukemic cells with ture with increased structure diminishing the HHT, the short-lived antiapoptotic protein efficiency of the eIF4E-cap interaction and/ Mcl-1 was observed to be rapidly degraded, an or imposing a structural barrier to the weak effect that was solely attributed to the acute loss eIF4A helicase activity (Pelletier and Sonenberg in overall protein synthesis and that was re- 1985b; Lawson et al. 1986). Consequently, al- versed upon proteasome inhibition (Tang et al. tering the levels of eIF4F can influence which 2006; Robert et al. 2009; Chen et al. 2011a). mRNAs are more readily translated (Lawson This, and perhaps the degradation of other et al. 1986, 1988), correlating with the degree short-lived prosurvival factors, explains some of secondary structure in the 50-untranslated of the synergistic effects observed with different regions (50-UTRs) of the mRNA—the greater inhibitors of translation elongation in the Bur- the thermal stability, the more poorly the tran- kitt’s-like Em-Myc lymphoma mouse model script is translated, presumably by obstruct- and would warrant greater study and further ing efficient ribosome loading and 48S complex 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a012377 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Therapeutics and Translational Control formation (Pelletier and Sonenberg 1985a,b; and 4E-BP2), which prevents them from dis- Lawson et al. 1986; Babendure et al. 2006). In- rupting the eIF4E/eIF4G interaction, and (2) creasing the amounts of cellular eIF4E can thus mTOR signals the degradation of PDCD4, disproportionately stimulate the expression of which interferes with the eIF4A/eIF4G interac- messages that were once outcompeted by un- tion (Gingras et al. 1999b; Dorrello et al. 2006). structured mRNAs, encoding proteins that are Thus, active mTOR promotes eIF4F formation often progrowth and prosurvival in nature. In and translation initiation. fact, this is thought to be the underlying mech- The identification of germline mutations in anism behind eIF4E’s tumorigenic properties, genes that encode negative regulators of mTOR the selective increase in translation of a limited signaling (e.g., Pten and Tsc1/2), the fact that set of oncogenic and metastatic transcripts (La- rapamycin possesses antiproliferative activity zaris-Karatzas et al. 1990; Ruggero et al. 2004; against a number of cancer cell lines (Hidalgo Wendel et al. 2004). The role that eIF4E plays in and Rowinsky 2000), and the observation that cancer has received much broader scientific and a majority of human cancers arise owing to clinical interest of late since the discovery that its activated mTORC1 signaling (Yuan and Cant- function is regulated by mTOR (mammalian ley 2008), emphasized the need to uncover the target of rapamycin), a master regulator of cel- role of mTOR in human cancer. Important- lular homeostasis and key signaling node often ly, it is well established that mTOR control of up-regulated in cancers, and that the chemo- eIF4F assembly acts as a critical node for can- therapeutic rapamycin, its highly specific inhib- cer cell survival and proliferation (Wendel et al. itor, can