Cap‐Dependent Translation Initiation Factor eIF4E: An Emerging Anticancer Drug Target

Cancer cells tend to be more highly dependent on cap‐dependent translation than normal tissues. Thus, proteins involved in the initiation of cap‐dependent translation have emerged as potential anti‐cancer drug targets. Cap‐dependent translation is initiated by the binding of the factor eIF4E to the cap domain of mRNA. Detailed x‐ray crystal and NMR structures are available for eIF4E in association with cap‐analogs, as well as domains of other initiation factors. This review will summarize efforts to design potential antagonist of eIF4E that could be used as new pharmacological tools and anti‐cancer agents and. Insights drawn from these studies should aid in the design of future inhibitors of eIF4E dependent translation initiation. © 2012 Wiley Periodicals, Inc. Med Res Rev., 32, No. 4, 786‐814, 2012

[1]  S. Vajda,et al.  Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F , 2010, Proceedings of the National Academy of Sciences.

[2]  P. Pandolfi,et al.  eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression , 2010, Proceedings of the National Academy of Sciences.

[3]  M. Yarmush,et al.  Lytic peptide-mediated sensitization of TRAIL-resistant prostate cancer cells to death receptor agonists. , 2010, Cancer letters.

[4]  R. Herbst,et al.  Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  F. Khuri,et al.  The eIF4E/eIF4G interaction inhibitor 4EGI-1 augments TRAIL-mediated apoptosis through c-FLIP Down-regulation and DR5 induction independent of inhibition of cap-dependent protein translation. , 2010, Neoplasia.

[6]  Elizabeth A. Amin,et al.  Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn7-GMP. , 2010, European journal of medicinal chemistry.

[7]  K. Shokat,et al.  Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. , 2010, Cancer cell.

[8]  B. Leber,et al.  Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin. , 2009, Blood.

[9]  S. Ko,et al.  Inhibition of Ovarian Cancer Growth by a Tumor-Targeting Peptide That Binds Eukaryotic Translation Initiation Factor 4E , 2009, Clinical Cancer Research.

[10]  C. Wagner,et al.  Nontoxic chemical interdiction of the epithelial-to-mesenchymal transition by targeting cap-dependent translation. , 2009, ACS chemical biology.

[11]  P. Gao,et al.  Tumor-specific RNAi targeting eIF4E suppresses tumor growth, induces apoptosis and enhances cisplatin cytotoxicity in human breast carcinoma cells , 2009, Breast Cancer Research and Treatment.

[12]  E. Herrmann,et al.  Ribavirin mode of action in chronic hepatitis C: from clinical use back to molecular mechanisms , 2008, Liver international : official journal of the International Association for the Study of the Liver.

[13]  R. Rhoads,et al.  Kinetic Mechanism for Assembly of the m7GpppG·eIF4E·eIF4G Complex* , 2008, Journal of Biological Chemistry.

[14]  P. Houghton,et al.  Effects of 4E-BP1 expression on hypoxic cell cycle inhibition and tumor cell proliferation and survival , 2008, Cancer biology & therapy.

[15]  S. Lowe,et al.  Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model. , 2008, The Journal of clinical investigation.

[16]  Gopal Singh,et al.  eIF4E knockdown decreases breast cancer cell growth without activating Akt signaling , 2008, Molecular Cancer Therapeutics.

[17]  A. Gingras,et al.  Control of eIF4E cellular localization by eIF4E-binding proteins, 4E-BPs. , 2008, RNA.

[18]  S. Liebhaber,et al.  Hypoxia-mediated Selective mRNA Translation by an Internal Ribosome Entry Site-independent Mechanism* , 2008, Journal of Biological Chemistry.

[19]  H. Wendel,et al.  MNK, EIF4E and targeting translation for therapy , 2008, Cell cycle.

[20]  J. Graff,et al.  Targeting the eukaryotic translation initiation factor 4E for cancer therapy. , 2008, Cancer research.

[21]  M. Bushell,et al.  Re‐programming of translation following cell stress allows IRES‐mediated translation to predominate , 2008, Biology of the cell.

[22]  S. Lowe,et al.  Dissecting eIF4E action in tumorigenesis. , 2007, Genes & development.

[23]  M. Holcik,et al.  Cap-independent regulation of gene expression in apoptosis. , 2007, Molecular bioSystems.

[24]  M. Walkinshaw,et al.  Crystallographic and mass spectrometric characterisation of eIF4E with N7-alkylated cap derivatives. , 2007, Journal of molecular biology.

[25]  Tao Wang,et al.  Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity. , 2007, The Journal of clinical investigation.

[26]  O. Larsson,et al.  Eukaryotic translation initiation factor 4E induced progression of primary human mammary epithelial cells along the cancer pathway is associated with targeted translational deregulation of oncogenic drivers and inhibitors. , 2007, Cancer research.

[27]  G. Giaccone,et al.  TRAIL therapy in non–small cell lung cancer cells: sensitization to death receptor–mediated apoptosis by proteasome inhibitor bortezomib , 2007, Molecular Cancer Therapeutics.

[28]  S. Knapp,et al.  Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms. , 2007, Journal of molecular biology.

[29]  Wan-Wan Lin,et al.  5-Aminoimidazole-4-carboxamide riboside sensitizes TRAIL- and TNFα-induced cytotoxicity in colon cancer cells through AMP-activated protein kinase signaling , 2007, Molecular Cancer Therapeutics.

[30]  D. Stuart,et al.  Reconfiguration of yeast 40S ribosomal subunit domains by the translation initiation multifactor complex , 2007, Proceedings of the National Academy of Sciences.

[31]  D. Spandidos,et al.  Chemotherapeutic drugs sensitize cancer cells to TRAIL-mediated apoptosis: up-regulation of DR5 and inhibition of Yin Yang 1 , 2007, Molecular Cancer Therapeutics.

[32]  A. Degterev,et al.  Small-Molecule Inhibition of the Interaction between the Translation Initiation Factors eIF4E and eIF4G , 2007, Cell.

[33]  N. Sonenberg,et al.  mTOR, translation initiation and cancer , 2006, Oncogene.

[34]  R. Rhoads,et al.  Stopped-flow Kinetic Analysis of eIF4E and Phosphorylated eIF4E Binding to Cap Analogs and Capped Oligoribonucleotides , 2006, Journal of Biological Chemistry.

[35]  R. Pieper,et al.  Translational Regulation of TRAIL Sensitivity , 2006, Cell cycle.

[36]  C. Gualerzi,et al.  Specific, efficient, and selective inhibition of prokaryotic translation initiation by a novel peptide antibiotic. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[37]  V. Polunovsky,et al.  The Cap-Dependent Translation Apparatus Integrates and Amplifies Cancer Pathways , 2006, RNA biology.

[38]  N. Sonenberg,et al.  mTOR signaling: implications for cancer and anticancer therapy , 2005, British Journal of Cancer.

[39]  Toshimasa Ishida,et al.  Structural basis for mRNA Cap-Binding regulation of eukaryotic initiation factor 4E by 4E-binding protein, studied by spectroscopic, X-ray crystal structural, and molecular dynamics simulation methods. , 2005, Biochimica et biophysica acta.

[40]  A. Kentsis,et al.  Further evidence that ribavirin interacts with eIF4E. , 2005, RNA.

[41]  L. Beeren,et al.  The antiviral drug ribavirin does not mimic the 7-methylguanosine moiety of the mRNA cap structure in vitro. , 2005, RNA.

[42]  M. Berger,et al.  mTOR Controls FLIPS Translation and TRAIL Sensitivity in Glioblastoma Multiforme Cells , 2005, Molecular and Cellular Biology.

[43]  D. Maeder,et al.  Phylogenetic analysis of eIF4E-family members , 2005, BMC Evolutionary Biology.

[44]  F. Khuri,et al.  Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. , 2005, Cancer research.

[45]  J. Pelletier,et al.  Ribavirin is not a functional mimic of the 7-methyl guanosine mRNA cap. , 2005, RNA.

[46]  E. De Clercq,et al.  Application of phosphoramidate pronucleotide technology to abacavir leads to a significant enhancement of antiviral potency. , 2005, Journal of medicinal chemistry.

[47]  C. Wagner,et al.  Synthesis and evaluation of potential inhibitors of eIF4E cap binding to 7-methyl GTP. , 2005, Bioorganic & medicinal chemistry letters.

[48]  C. Hagedorn,et al.  A mutant of eukaryotic protein synthesis initiation factor eIF4E(K119A) has an increased binding affinity for both m7G cap analogues and eIF4G peptides. , 2005, Biochemistry.

[49]  A. Kentsis,et al.  Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[50]  A. Ashkenazi,et al.  Targeting death receptors in cancer with Apo2L/TRAIL. , 2004, Current opinion in pharmacology.

[51]  A. Amoroso,et al.  The role of ribavirin in the combination therapy of hepatitis C virus infection. , 2004, Current pharmaceutical design.

[52]  Amy R. Cameron,et al.  Characterization of mammalian eIF4E-family members. , 2004, European journal of biochemistry.

[53]  N. Sonenberg,et al.  Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. , 2004, Cancer cell.

[54]  Isabelle Bougie,et al.  The Broad Spectrum Antiviral Nucleoside Ribavirin as a Substrate for a Viral RNA Capping Enzyme* , 2004, Journal of Biological Chemistry.

[55]  W. Merrick.  Cap-dependent and cap-independent translation in eukaryotic systems. , 2004, Gene.

[56]  J. Stȩpiński,et al.  Influence of electric charge variation at residues 209 and 159 on the interaction of eIF4E with the mRNA 5' terminus. , 2004, Biochemistry.

[57]  P. Pandolfi,et al.  The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis , 2004, Nature Medicine.

[58]  J. Graff,et al.  eIF-4E expression and its role in malignancies and metastases , 2004, Oncogene.

[59]  S. Lowe,et al.  Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy , 2004, Nature.

[60]  P. Linder,et al.  DEAD-box proteins: the driving forces behind RNA metabolism , 2004, Nature Reviews Molecular Cell Biology.

[61]  J. Pelletier,et al.  Inhibitors of protein synthesis identified by a high throughput multiplexed translation screen. , 2004, Nucleic acids research.

[62]  G. Wagner,et al.  Ribosome Loading onto the mRNA Cap Is Driven by Conformational Coupling between eIF4G and eIF4E , 2003, Cell.

[63]  N. Dean,et al.  Antisense oligonucleotide-based therapeutics for cancer , 2003, Oncogene.

[64]  W. Merrick.  Initiation of protein biosynthesis in eukaryotes , 2003 .

[65]  R. Rhoads,et al.  Novel "anti-reverse" cap analogs with superior translational properties. , 2003, RNA.

[66]  C. Wagner,et al.  Disposition and Oral Bioavailability in Rats of an Antiviral and Antitumor Amino Acid Phosphoramidate Prodrug of AZT-Monophosphate , 2003, Pharmaceutical Research.

[67]  J. Antosiewicz,et al.  Effects of pH on kinetics of binding of mRNA-cap analogs by translation initiation factor eIF4E , 2003, European Biophysics Journal.

[68]  J. Humphrey,et al.  Cancer Drug Discovery and Development , 2002 .

[69]  Daniel R. Gallie,et al.  Protein-protein interactions required during translation , 2002, Plant Molecular Biology.

[70]  Nahum Sonenberg,et al.  Positive heat capacity change upon specific binding of translation initiation factor eIF4E to mRNA 5' cap. , 2002, Biochemistry.

[71]  Anne-Claude Gingras,et al.  Biophysical studies of eIF4E cap-binding protein: recognition of mRNA 5' cap structure and synthetic fragments of eIF4G and 4E-BP1 proteins. , 2002, Journal of molecular biology.

[72]  C. Wagner,et al.  Pharmacokinetics of Amino Acid Phosphoramidate Monoesters of Zidovudine in Rats , 2002, Antimicrobial Agents and Chemotherapy.

[73]  C. Norbury,et al.  Translation initiation and its deregulation during tumorigenesis , 2002, British Journal of Cancer.

[74]  A. Gingras,et al.  Translational Control of Cell Fate: Availability of Phosphorylation Sites on Translational Repressor 4E-BP1 Governs Its Proapoptotic Potency , 2002, Molecular and Cellular Biology.

[75]  C. Rudin,et al.  Phase I clinical and pharmacokinetic study of protein kinase C-alpha antisense oligonucleotide ISIS 3521 administered in combination with 5-fluorouracil and leucovorin in patients with advanced cancer. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[76]  K. Tomoo,et al.  Crystal structures of 7-methylguanosine 5'-triphosphate (m(7)GTP)- and P(1)-7-methylguanosine-P(3)-adenosine-5',5'-triphosphate (m(7)GpppA)-bound human full-length eukaryotic initiation factor 4E: biological importance of the C-terminal flexible region. , 2002, The Biochemical journal.

[77]  G. Scheper,et al.  Phosphorylation of Eukaryotic Initiation Factor 4E Markedly Reduces Its Affinity for Capped mRNA* , 2002, The Journal of Biological Chemistry.

[78]  C. Cameron,et al.  Hepatitis C Virus RNA-dependent RNA Polymerase (NS5B) as a Mediator of the Antiviral Activity of Ribavirin* , 2001, The Journal of Biological Chemistry.

[79]  R. Rhoads,et al.  Synthesis and properties of mRNAs containing the novel "anti-reverse" cap analogs 7-methyl(3'-O-methyl)GpppG and 7-methyl (3'-deoxy)GpppG. , 2001, RNA.

[80]  Z. Hong,et al.  Mechanisms of Action of Ribavirin in Antiviral Therapies , 2001, Antiviral chemistry & chemotherapy.

[81]  A. Kentsis,et al.  The RING domains of the promyelocytic leukemia protein PML and the arenaviral protein Z repress translation by directly inhibiting translation initiation factor eIF4E. , 2001, Journal of molecular biology.

[82]  W. Merrick,et al.  Modulation of the Helicase Activity of eIF4A by eIF4B, eIF4H, and eIF4F* , 2001, The Journal of Biological Chemistry.

[83]  C. Cameron,et al.  RNA virus error catastrophe: Direct molecular test by using ribavirin , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[84]  C. Wagner,et al.  Amino acid phosphoramidate monoesters of 3'-azido-3'-deoxythymidine: relationship between antiviral potency and intracellular metabolism. , 2001, Journal of medicinal chemistry.

[85]  J. Arnold,et al.  The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen , 2000, Nature Medicine.

[86]  C. Wagner,et al.  Pronucleotides: Toward the in vivo delivery of antiviral and anticancer nucleotides , 2000, Medicinal research reviews.

[87]  J. McCarthy,et al.  Stabilization of Eukaryotic Initiation Factor 4E Binding to the mRNA 5′-Cap by Domains of eIF4G* , 2000, The Journal of Biological Chemistry.

[88]  J. Antosiewicz,et al.  Stopped-flow and Brownian dynamics studies of electrostatic effects in the kinetics of binding of 7-methyl-GpppG to the protein eIF4E , 2000, European Biophysics Journal.

[89]  Rosie Yu,et al.  Reduction of liver Fas expression by an antisense oligonucleotide protects mice from fulminant hepatitis , 2000, Nature Biotechnology.

[90]  F. Natt,et al.  A novel bispecific antisense oligonucleotide inhibiting both bcl-2 and bcl-xL expression efficiently induces apoptosis in tumor cells. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[91]  S. Zimmer,et al.  Translational control of malignancy: the mRNA cap-binding protein, eIF-4E, as a central regulator of tumor formation, growth, invasion and metastasis. , 2000, Anticancer research.

[92]  R. Rhoads,et al.  Quantitative assessment of mRNA cap analogues as inhibitors of in vitro translation. , 1999, Biochemistry.

[93]  A. Gingras,et al.  Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G. , 1999, Molecular cell.

[94]  C. Wagner,et al.  Antiviral nucleoside drug delivery via amino acid phosphoramidates. , 1999, Nucleosides & nucleotides.

[95]  Jonathan A. Cooper,et al.  Phosphorylation of the Cap-Binding Protein Eukaryotic Translation Initiation Factor 4E by Protein Kinase Mnk1 In Vivo , 1999, Molecular and Cellular Biology.

[96]  J. McCarthy,et al.  Cooperative modulation by eIF4G of eIF4E‐binding to the mRNA 5′ cap in yeast involves a site partially shared by p20 , 1998, The EMBO journal.

[97]  D. Gallie.  A tale of two termini: a functional interaction between the termini of an mRNA is a prerequisite for efficient translation initiation. , 1998, Gene.

[98]  A. Gingras,et al.  4E-BP3, a New Member of the Eukaryotic Initiation Factor 4E-binding Protein Family* , 1998, The Journal of Biological Chemistry.

[99]  A. Gingras,et al.  Structure of translation factor elF4E bound to m7GDP and interaction with 4E-binding protein , 1997, Nature Structural Biology.

[100]  N. Sonenberg,et al.  eIF4G Dramatically Enhances the Binding of eIF4E to the mRNA 5′-Cap Structure* , 1997, The Journal of Biological Chemistry.

[101]  Benjamin D. L. Li,et al.  Elevated expression of eIF4E and FGF-2 isoforms during vascularization of breast carcinomas , 1997, Oncogene.

[102]  A. De Benedetti,et al.  Overexpression of eukaryotic initiation factor 4E (eIF4E) in breast carcinoma , 1997, Cancer.

[103]  A. Gingras,et al.  Cocrystal Structure of the Messenger RNA 5′ Cap-Binding Protein (eIF4E) Bound to 7-methyl-GDP , 1997, Cell.

[104]  Jonathan A. Cooper,et al.  Mitogen‐activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2 , 1997, The EMBO journal.

[105]  S. Crooke.  Progress in antisense therapeutics. , 1996, Hematologic pathology.

[106]  K. Browning.  The plant translational apparatus , 1996, Plant Molecular Biology.

[107]  R. Rhoads,et al.  Phosphorylation of Eukaryotic Protein Synthesis Initiation Factor 4E at Ser-209 (*) , 1995, The Journal of Biological Chemistry.

[108]  N. Sonenberg,et al.  mRNAs containing extensive secondary structure in their 5′ non‐coding region translate efficiently in cells overexpressing initiation factor eIF‐4E. , 1992, The EMBO journal.

[109]  J. Wall,et al.  Image analysis of Artemia salina ribosomes by scanning transmission electron microscopy. , 1992, Journal of structural biology.

[110]  D. Goss,et al.  Wheat germ initiation factors 4F and (iso)4F interact differently with oligoribonucleotide analogues of rabbit alpha-globin mRNA. , 1991, Biochemistry.

[111]  A. De Benedetti,et al.  Overexpression of eukaryotic protein synthesis initiation factor 4E in HeLa cells results in aberrant growth and morphology. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[112]  R. Rhoads,et al.  A fluorescence study of the interaction of protein synthesis initiation factors 4A, 4E, and 4F with mRNA and oligonucleotide analogs. , 1990, Biochimica et biophysica acta.

[113]  R. Rhoads,et al.  A spectroscopic study of the binding of m7GTP and m7GpppG to human protein synthesis initiation factor 4E. , 1989, Biochemistry.

[114]  N. Sonenberg,et al.  Inhibition of eukaryotic translation by nucleoside 5'-monophosphate analogues of mRNA 5'-cap: changes in N7 substituent affect analogue activity. , 1989, Biochemistry.

[115]  I. Ekiel,et al.  Inhibition of eukaryotic translation by analogues of messenger RNA 5'-cap: chemical and biological consequences of 5'-phosphate modifications of 7-methylguanosine 5'-monophosphate. , 1987, Biochemistry.

[116]  R. Smith,et al.  The broad spectrum antiviral agent ribavirin inhibits capping of mRNA. , 1979, Biochemical and biophysical research communications.

[117]  W. Müller,et al.  Virazole (1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide; A cytostatic agent , 1977 .

[118]  R. K. Robins,et al.  THE RELATIONSHIP BETWEEN THE METABOLISM OF RIBAVIRIN AND ITS PROPOSED MECHANISM OF ACTION , 1977, Annals of the New York Academy of Sciences.

[119]  R. J. Bauer,et al.  Mechanism of action of 1- -D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole), a new broad-spectrum antiviral agent. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[120]  R. K. Robins,et al.  Broad-Spectrum Antiviral Activity of Virazole: 1-f8- D-Ribofuranosyl- 1,2,4-triazole- 3-carboxamide , 1972, Science.

[121]  V. Polunovsky,et al.  Translational Control of Cancer: Implications for Targeted Therapy , 2009 .

[122]  A. Gingras,et al.  Eukaryotic Translation Initiation Factor 4E Availability Controls the Switch between Cap-Dependent and Internal Ribosomal Entry Site-Mediated Translation† , 2005 .

[123]  M. López-Lastra,et al.  Protein synthesis in eukaryotes: the growing biological relevance of cap-independent translation initiation. , 2005, Biological research.

[124]  A. Levin,et al.  Tissue disposition of 2'-O-(2-methoxy) ethyl modified antisense oligonucleotides in monkeys. , 2004, Journal of pharmaceutical sciences.

[125]  C. Rudin,et al.  Phase I clinical and pharmacokinetic study of protein kinase C-alpha antisense oligonucleotide ISIS 3521 administered in combination with 5-fluorouracil and leucovorin in patients with advanced cancer. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[126]  A. Gingras,et al.  eIF4E activity is regulated at multiple levels. , 1999, The international journal of biochemistry & cell biology.

[127]  A. Gingras,et al.  eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. , 1999, Annual review of biochemistry.

[128]  A. De Benedetti,et al.  eIF4E expression in tumors: its possible role in progression of malignancies. , 1999, The international journal of biochemistry & cell biology.

[129]  E. De Clercq,et al.  Antiviral agents: characteristic activity spectrum depending on the molecular target with which they interact. , 1993, Advances in virus research.

[130]  J. Connor,et al.  The metabolism of ribavirin in erythrocytes and nucleated cells. , 1990, The International journal of biochemistry.

[131]  W. Müller,et al.  Virazole (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide; a cytostatic agent. , 1977, Biochemical pharmacology.

[132]  J. Vandesompele,et al.  Bmc Developmental Biology Identification and Expression Analysis of Genes Associated with Bovine Blastocyst Formation , 2022 .