The Eif4f Translation Initiation Complex—New Opportunities For

Published OnlineFirst October 27, 2016; DOI: 10.1158/1078-0432.CCR-14-2362

Molecular Pathways Clinical Cancer Research Molecular Pathways: The eIF4F Translation Initiation Complex—New Opportunities for Cancer Treatment Hel ene Malka-Mahieu1,2,3, Michelle Newman1,2,3, Laurent Desaubry 4,5, Caroline Robert6,7,8, and Stephan Vagner1,2,3,6,7

Abstract

The eIF4F complex regulates the cap-dependent mRNA complex components can restore sensitivity to various cancer translation process. It is becoming increasingly evident that therapies. Here, we review the contribution of the eIF4F aberrant activity of this complex is observed in many cancers, complex to tumorigenesis, with a focus on its role in che- leading to the selective synthesis of proteins involved in tumor moresistance as well as the promising use of new small- growth and metastasis. The selective translation of cellular molecule inhibitors of the complex, including ﬂavaglines/ mRNAs controlled by this complex also contributes to resis- rocaglates, hippuristanol, and pateamine A. Clin Cancer Res; tance to cancer treatments, and downregulation of the eIF4F 23(1); 21–25. 2016 AACR.

Background protein, the eIF4A DEAD box RNA helicase, and the eIF4G scaffolding protein (Fig. 1A). eIF4A utilizes ATP hydrolysis to Among the different steps in gene expression, cytoplasmic unwind and resolve RNA secondary structures. Although ATP mRNA translation is an essential process that leads to protein hydrolysis is necessary to the unwinding action, it also releases synthesis. Although global translation rates are generally higher in eIF4A from the mRNA, meaning it can use another substrate and, cancer cells, it is now acknowledged that subsets of mRNAs are thus, recycle the available eIF4A to increase the rate of translation. speciﬁcally regulated at the translation level. Excellent reviews Finally, eIF4G is a scaffold protein for the assembly of the eIF4F have recently been published on the role of translation in cancer complex. The activity of the eIF4F complex is tightly controlled by (1–5). Here, we focus on the eIF4F complex, its role in chemore- its interaction with several proteins, including the eIF4A-binding sistance, and its targeting with small-molecule inhibitors. proteins eIF4B, eIF4H, and programmed cell death 4 (PDCD4; The interaction between eIF4F and the 7-methylguanosine eIF4B and eIF4H stimulate, whereas PDCD4 inhibits eIF4A); the "cap" (m7G) located at the 50 end of all mRNAs is critical to eIF4E-inhibitory proteins 4EBP1–3; and many eIF4G-interacting directly recruit the 40S ribosomal subunit to mRNAs through a set proteins (e.g., the poly(A) binding protein PABP). of protein–protein interactions and to unwind RNA secondary Not all mRNAs are similarly selected by the eIF4F complex. structures located in the 50 untranslated region (50UTR) of eIF4E is implicated in the translation of long and highly structured mRNAs. The eIF4F complex comprises the eIF4E cap-binding mRNAs. Of these mRNAs, many encode proteins involved in cell-cycle progression, cell growth, or angiogenesis (e.g., MYC, CCDN1, ODC1, VEGF, FGF2) or more generally cancer-related 1Institut Curie, PSL Research University, CNRS UMR 3348, Orsay, France. 2Uni- versite Paris Sud, Universite Paris-Saclay, CNRS UMR 3348, Orsay, France. genes (2). The mRNAs that require eIF4A for their translation were 3Equipe Labellisee Ligue Contre le Cancer, Paris, France. 4Laboratory of Ther- characterized using transcriptome-scale ribosome footprinting apeutic Innovation (UMR 7200), Faculty of Pharmacy, University of Strasbourg– (6). Such mRNAs, which are limited in number, harbor a partic- 0 CNRS, Illkirch, France. 5Sino-French Joint Lab of Food Nutrition/Safety and ularly long 5 UTR with guanine-rich motifs that form G-quad- Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and ruplexes, such as the 12-nucleotide (CGG)4 motif, that form a 6 7 Technology, Tianjin, China. INSERM U981, Villejuif, France. Institut de 4-stranded structure. Importantly, most of these mRNAs encode Cancerologie Gustave Roussy, Villejuif, France. 8Universite Paris-Sud, Krem- for oncogenes, transcription factors, epigenetic regulators, and lin-Bicetre,^ France. kinases, whereas housekeeping genes do not display G-quadru- Note: Supplementary data for this article are available at Clinical Cancer plexes and do not require eIF4A for their translation. Research Online (http://clincancerres.aacrjournals.org/). The eIF4F complex is located at the convergence of several cell H. Malka-Mahieu and M. Newman share ﬁrst authorship. signaling pathways involved in carcinogenesis, including the Corresponding Authors: Stephan Vagner, Institut Curie, Universite Paris XI, PI(3)K/AKT/mTOR pathway and the RAS/RAF/MEK/ERK/MNK Orsay 91405, France. Phone: 331-6986-3103; Fax: 331-6986-9429; E-mail: MAPK pathway (Fig. 1B). When phosphorylated by mTORC1, the [email protected]; and Caroline Robert, INSERM U981, Gustave Roussy, 4EBP proteins are unable to bind eIF4E, enabling the formation of 114, rue Edouard-Vaillant, Villejuif 94805, France. Phone: 331-4211-4211; E-mail: an effective eIF4E–eIF4G complex. mTORC1 is also responsible for [email protected] the phosphorylation of the S6K1/2 kinases, which phosphorylate doi: 10.1158/1078-0432.CCR-14-2362 (i) the eIF4A-inhibitory protein PDCD4, relieving the inhibitory 2016 American Association for Cancer Research. activity of PDCD4 on eIF4A, and (ii) eIF4B, allowing it to interact

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Malka-Mahieu et al.

A mRNA

cap 4EBP ORF Poly(A) eIF4E 5'UTR 3'UTR 1/2/3

eIF4A PDCD4 eIF4G eIF4F complex eIF4B

Figure 1. eIF4H Convergence of major signaling pathways involved in cancer toward the eIF4F complex. A, The eIF4F complex comprises three proteins: the B cap-binding protein eIF4E, the DEAD Lapatinib Lapatinib box RNA helicase eIF4A, and the Cetuximab Neratinib scaffolding protein eIF4G. This Erlotinib Trastuzumab Lucitanib Gefitinib complex is negatively regulated by Dovitnib Panitumumab HER2 PI(3)K 4EBP1–3 (eIF4E inhibitors) and PDCD4 AZD4547 (eIF4A inhibitor) and actively EGFR BGJ398 regulated by eIF4B and eIF4H (eIF4A Brivanib FGFR TGFβ-R PTEN cofactors). B, The eIF4F complex TNFR BEZ235 Lenvatinib comprising eIF4E, eIF4G, and eIF4A is XL765 Motesanib AKT regulated by the MAPK pathway, the VEGFR BGT226 Pazopanib PI(3)K/AKT/mTOR pathway, and Regorafenib SMAD4 NF-κB mTOR transcription factors located Rapamycin downstream of receptor tyrosine C/EBPα Everolimus kinases (RTK). Aberrant activation of Temsirolimus RAS one of these pathways leads to HIFα AZD8055 Trametinib 4EBP1 oncogenic processes. Consequently, Cobimetinib eIF4E many inhibitors (red text) have been AZD6244 MYC designed to specifically inhibit RTKs or PD0325901 C/EBPβ components of the MAPK or PI(3)K/ 4EGI-1 RAF ERKMEK MNK 4E-ASO mTOR pathways. The majority of 4E1RCat Sp1 inhibitors indicated in the figure have Vemurafenib Cercosporamide 4E2RCat eIF4G Hippuristanol several targets; however, only the main Dabrafenib CGP57380 Ets eIF4B Pateamine A one is indicated. eIF4F is positioned Silvestrol at the convergence of these RSK FL3 MYC dysregulated pathways and is, eIF4A therefore, a promising target for S6 PDCD4 many types of cancer.

S6K RSK

with eIF4A to enhance its helicase activity. In the MAPK path- tion of eIF4E on a single site (Ser209) through its interaction way, ERK inﬂuences the translation via the activation of the RSK with eIF4G. Strong evidence links eIF4E phosphorylation with kinases that target PDCD4 and S6, independently of the S6K tumorigenesis, invasion, and metastatic progression in cells and kinases. MNK, downstream of ERK, controls the phosphoryla- in mouse models (7–10).

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eIF4F and Cancer

In parallel with these phosphorylation events, the expression factor in this process (Supplementary Table S1). This aspect will of the eIF4F complex components is also regulated. For instance, be expanded further in the following section. the MYC transcription factor, one of the most frequently activated eIF4A cofactors, eIF4B and eIF4H, are also involved in chemo- oncogenes in human cancers, increases the transcription of all sensitivity. Overexpression of both eIF4H isoforms inhibited genes encoding components of the eIF4F complex (eIF4E, eIF4A, caspase activity following cisplatin and etoposide treatment in and eIF4G), thereby controlling protein translation. Other tran- murine NIH3T3 cells (20). In addition, eIF4B is overexpressed in scription factors can also regulate the transcription of the individ- cisplatin/fluorouracil-resistant gastric tumors (21). Finally, resis- ual components of the translation complex following stimulation tance to anti-BRAF and anti-MEK therapies is associated with a by various growth factor pathways (Supplementary Table S1). prominently active eIF4F complex in a BRAF(V600)-mutated The eIF4F complex contributes to many of the hallmarks context (22). of cancer, such as sustained proliferative signaling, evasion of growth suppression, resistance to programmed cell death, repli- Inhibitors of the eIF4F complex cative immortality, angiogenesis, invasion, and metastasis. Each The first strategy to decrease eIF4F activity has been to target of the individual components of the complex has been described eIF4E, which is the least abundant factor of the complex. Targeting as a prognostic indicator. Expression levels of the eIF4F complex eIF4E with an antisense oligonucleotide (4EASO) has shown a components and their inhibitors as well as phosphorylation significant antineoplastic effect, where tumor growth in a prostate can be linked with the aggressiveness of histological subtypes of xenograft model was suppressed, as was the formation of vessel- cancers, poor disease outcome and survival, and response to like structures, suggesting an additional antiangiogenic effect treatment (Supplementary Table S2). (23). Clinical trials with this inhibitor produced few adverse effects but no significant clinical response on tumors (24). There- Clinical–Translational Advances fore, although targeting eIF4E appears to be an attractive treatment, its effect as a single agent, at least using the aforementioned eIF4F and resistance to anticancer therapies antisense technology, was not effective. During the last decade, it has been demonstrated that the Another strategy to block eIF4E activity is to target the eIF4E– activity of the eIF4F complex contributes to drive resistance to cap interaction. The pronucleotide 4Ei-1 (N-7 benzyl guanosine many types of therapies used as treatment in cancer. One of the monophosphate tryptamine phosphoramidate pronucleotide) in first examples was shown in Em-MYC hematopoietic stem cells combination with nontoxic levels of gemcitabine has been trialed transfected with retroviral vectors expressing eIF4E. Lymphoma in breast and lung cancer cells, which resulted in chemosensitiza- cells overexpressing the cap-binding protein are highly resistant to tion of the cell lines (25). the DNA-damaging agent doxorubicin compared with controls Specifically disrupting the eIF4E–eIF4G interaction has yielded (11), and this observation has since been extended to other types promising results. The first compound used was 4EGI-1, identi- of therapies. Knockdown of eIF4E results in enhanced chemo- fied by a high-throughput screening assay in 2007 (26). This drug sensitivity to cisplatin and antimitotic microtubule stabilizers induced apoptotic cell death in several tumor cell lines in vitro (26, (e.g., paclitaxel, docetaxel) in triple-negative breast cancer cells 27) and promoted tumor regression of breast or melanoma cancer (12). In addition, increased expression of miR141, which targets xenografts in vivo (28), whereas another eIF4E–eIF4G inhibitor, eIF4E, has also been observed in an acquired model of docetaxel 4E1RCat, promoted tumor-free survival when used in combina- resistance in breast cancer (13). tion with doxorubicin (29). eIF4E overexpression or amplification also promotes resistance Three classes of eIF4A inhibitors have been reported so far. to PI(3)K/AKT/mTOR inhibitors (e.g., AZD8055, BEZ235) in Flavaglines, hippuristanol, and pateamine A all originate from immortalized mammary epithelial cells or colon cancer cells natural products that display potent anticancer effects in vivo. (14, 15), and ectopic expression of eIF4E leads to resistance to Rocaglamide (flavaglines) was isolated in 1982 from Asian inhibitors of receptor tyrosine kinases (e.g., trastuzumab, cetux- medicinal plants based on their potent antileukemic activities imab, erlotinib) in breast cancer xenografts (16). (30). Since then, more than 100 natural flavaglines, such as Furthermore, phosphorylation of eIF4E has been implicated in rocaglaol or silvestrol, have been identified, and many have been resistance to cisplatin in breast cancer cell lines and immortalized shown to display potent anticancer effects in murine cancer keratinocytes. Interestingly, this resistance to cisplatin is abol- models (31, 32). The most studied is silvestrol; unfortunately, ished in cancer cells that no longer have an interaction between p- this compound shows poor bioavailability coupled with high eIF4E and 4E-T, which mediates eIF4E nuclear import, indicating sensitivity to multidrug resistance (33). Gratifyingly, more drug- that phosphorylation of eIF4E and its interaction with 4E-T are like compounds that are insensitive to multidrug resistance dis- involved in the tolerance to increased DNA damage (17). playing enhanced in vivo anticancer activities have been reported. The eIF4A-inhibitory protein PDCD4 can also contribute to For instance, FL3 was shown to overcome the resistance to BRAF chemoresistance. Indeed, reexpression of PDCD4 sensitizes glio- inhibitors in mouse models of metastatic melanoma (22). blastoma multiforme cells to doxorubicin via Bcl-xL inhibition Many of the studies listed in Supplementary Table S3 have (18), and, conversely, low PDCD4 expression is associated with demonstrated that flavaglines strongly potentiate in vivo the resistance to paclitaxel and doxorubicin (19). antitumor effects of chemotherapeutic agents, in particular in eIF4A itself is not directly involved in resistance mechanisms, mouse models of chemoresistant cancers. but deregulation of its activity leads to chemosensitivity in many Remarkably, flavaglines have also been shown to bind the cancer types, as illustrated in Supplementary Table S1. Inhibition scaffold proteins prohibitins, blocking their interaction with of eIF4A binding to mRNA, of its recycling, or increase of its CRAF, which results in inhibition of the RAS/CRAF/MEK/ERK ATPase activity contributes to sensitization in many murine signaling pathway that is critical to the survival of the cancer cancer models and highlights the importance of this initiation cells (34). However, the identification of a drug-resistant and

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Malka-Mahieu et al.

functional eIF4A1 allele that abolishes the cytotoxicity of flava- development. It will be important to define biomarkers to deter- glines upon introduction into cells using the CRISPR/Cas9 tech- mine which subgroup of patients will be sensitive to these nology suggests that eIF4A is the prime target of flavaglines in inhibitors. Some reports are already showing that response to most of the cancers (35). treatment can be predicted using the eIF4F complex, and using Flavaglines were shown to block eIF4A recycling due to its prognostic factors combined with newer inhibitors may yield increased binding to mRNAs (36). The direct interaction with better responses to treatment. eIF4A was shown using affinity chromatography (37) and Although targeting eIF4E has shown impressive effects on chemogenomic profiling in yeast (38). As mentioned in the tumor progression in vivo, its clinical application has to be previous section, mRNAs that require eIF4A for their translation improved. Combining eIF4E inhibitors with other therapies encode for cancer-related proteins. Hence, this observation seems a promising strategy to be tested [phase II trials of 4E-ASO clarifies why eIF4A inhibitors display a cytotoxicity that is in combination with established chemotherapies are ongoing specific to cancer cells. In contrast, it has been shown that (NCT01234038 and NCT01234025)]. Furthermore, the use of flavagline sensitivity is poorly related to the presence of the both in vitro assays and in vivo mouse models are paving the way to G-quadruplexes in the 50UTR but depends strongly on poly- develop new combinations of eIF4F inhibitors with validated purine sequences in these regions (39). chemotherapies. Hippuristanol is a complex polyoxygenated steroid originally The reviewed studies on flavaglines, hippuristanol, and patea- isolated in 1981 from coral (40). This compound allosterically mine A strongly suggest that eIF4A is a valid target in oncology. inhibits the binding of mRNA to eIF4A (41, 42). Recent biophys- The promise of these compounds is poised to promote the ical studies using FRET indicate that hippuristanol locks eIF4AI in advancement of derivatives of these natural products toward the a closed conformation to inhibit RNA unwinding (43). In vivo clinic. It also highlights the resurgence of natural products in studies showed that hippuristanol significantly inhibits the oncology. Indeed, the advent of targeted therapies in the 1990s growth of primary effusion lymphoma in xenograft mice (44), placed the clinical study of anticancer agents from natural pro- suppresses T-cell tumor growth (45), and induces a synergistic ducts in limbo for a decade, until it appeared that targeted response with a Bcl-2 inhibitor (ABT-737), resulting in the induc- therapies would not fulfill expectations for many solid tumors. tion of apoptosis in lymphoma or leukemia cells (46). Hippur- Thus, since 2007, 12 novel natural product derivatives have been istanol has also been shown to induce cell-cycle arrest and approved to treat cancers, indicating that natural products con- apoptosis in vitro by reducing the expression of cell-cycle regula- tinue to provide valid opportunities to treat unmet medical needs. tors (such as cyclin D1/D2, CDK4, and CDK6) or prosurvival factors (such as Bcl-xl; ref. 45). Moreover, it is capable of reversing Disclosure of Potential Conflicts of Interest drug resistance in PI(3)K/AKT/mTOR-dependent tumors (46). No potential conflicts of interest were disclosed. Pateamine A is a complex macrolide that was isolated from a marine sponge in 1991 and demonstrated in vitro cytotoxicity against leukemia cells (47). Pateamine A prevents eIF4A hetero- Authors' Contributions dimerization with eIF4G but, surprisingly, enhances the helicase Conception and design: H. Malka-Mahieu, M. Newman, C. Robert, S. Vagner and ATPase activities of eIF4A (48, 49). Exploration of the struc- Writing, review, and/or revision of the manuscript: H. Malka-Mahieu, tural requirements of pateamine A for its pharmacologic activities M. Newman, L. Desaubry, C. Robert, S. Vagner Study supervision: S. Vagner led to the identification of desmethyl, desamino pateamine A as a structurally simplified analogue that significantly induced tumor regression in two mouse models of melanoma (50). Acknowledgments We apologize to all the colleagues who have made contributions in the field Conclusions and could not be cited owing to space constraints.

On the basis of their consistent anticancer activity, eIF4F Received July 1, 2016; revised September 7, 2016; accepted September 13, complex inhibitors should be considered for further clinical 2016; published OnlineFirst October 27, 2016.

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Molecular Pathways: The eIF4F Translation Initiation Complex−− New Opportunities for Cancer Treatment

Hélène Malka-Mahieu, Michelle Newman, Laurent Désaubry, et al.

Clin Cancer Res 2017;23:21-25. Published OnlineFirst October 27, 2016.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-14-2362

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