Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn7-GMP

Jia, Yan; Chiu, Ting Lan; Amin, Elizabeth A.; Polunovsky, Vitaly A.; Bitterman, Peter B.; Wagner, Carston R.

doi:10.1016/j.ejmech.2009.11.054

Cited by 43 publications

(48 citation statements)

References 42 publications

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“…Mutation of the cap-binding site of eIF4E impairs its activities in translation, mRNA export, and oncogenic transformation (12). Targeting the eIF4E-cap complex with a competitive m 7 G cap inhibitor is a promising strategy to generate anticancer agents (13,14). One such inhibitor, ribavirin, has reached clinical trials where it was used in poor-prognosis leukemia patients.…”

mentioning

confidence: 99%

eIF4E3 acts as a tumor suppressor by utilizing an atypical mode of methyl-7-guanosine cap recognition

Osborne

Volpon

Kornblatt

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

104

143

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Recognition of the methyl-7-guanosine (m 7 G) cap structure on mRNA is an essential feature of mRNA metabolism and thus gene expression. Eukaryotic translation initiation factor 4E (eIF4E) promotes translation, mRNA export, proliferation, and oncogenic transformation dependent on this cap-binding activity. eIF4E-cap recognition is mediated via complementary charge interactions of the positively charged m 7 G cap between the negative π-electron clouds from two aromatic residues. Here, we demonstrate that a variant subfamily, eIF4E3, specifically binds the m 7 G cap in the absence of an aromatic sandwich, using instead a different spatial arrangement of residues to provide the necessary electrostatic and van der Waals contacts. Contacts are much more extensive between eIF4E3-cap than other family members. Structural analyses of other cap-binding proteins indicate this recognition mode is atypical. We demonstrate that eIF4E3 relies on this cap-binding activity to act as a tumor suppressor, competing with the growthpromoting functions of eIF4E. In fact, reduced eIF4E3 in high eIF4E cancers suggests that eIF4E3 underlies a clinically relevant inhibitory mechanism that is lost in some malignancies. Taken together, there is more structural plasticity in cap recognition than previously thought, and this is physiologically relevant.M etabolism of mRNA is a complex and highly regulated process dependent on the association of the methyl-7-guanosine (m 7 G) cap structure on the 5′ end of transcripts with appropriate proteins (1-3). In mammalian cells, the two major cap-binding proteins are the nuclear cap-binding complex (CBC) (4) and eukaryotic translation initiation factor 4E (eIF4E) (3). Specific cap recognition is key for the fate of transcripts and impacts processes such as mRNA processing and bulk mRNA export via the CBC or the nuclear export of specific transcripts as well as bulk translation by eIF4E (5). NMR and crystallographic studies reveal that m 7 G cap is specifically recognized by both the CBC and eIF4E via intercalation of the m 7 G cap moiety with the side chains of two aromatic residues, i.e., an aromatic sandwich (4, 6-9). This is an electrostatically driven process relying on the partial positive charge of the m 7 G cap and the negative π-electron clouds of the aromatic residues. The aromatic residues are completely conserved in these cap-binding proteins. This recognition motif is used almost exclusively by proteins that specifically bind the m 7 G cap including eIF4E, CBC, and vaccinia virus protein VP39 (4, 10).Dysregulation of cap-binding proteins can have striking physiological consequences. For instance through its cap-binding activity and subsequent effects on gene expression, eIF4E plays an important role in proliferation and survival (1, 3). Indeed, eIF4E is overexpressed in about 30% of human cancers and its overexpression is oncogenic in cell culture and animal models (2, 11). Mutation of the cap-binding site of eIF4E impairs its activities in translation, mRNA export, and oncogenic transform...

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mentioning

confidence: 99%

eIF4E3 acts as a tumor suppressor by utilizing an atypical mode of methyl-7-guanosine cap recognition

Osborne

Volpon

Kornblatt

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

104

143

View full text Add to dashboard Cite

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“…Extensive work has been done establishing eIF4E as an oncogene; hence, different strategies are being employed to target eIF4E either directly through the use of ASOs 27 or through the use of small-molecule inhibitors, which inhibit either the eIF4E-eIF4G interaction [19][20][21] or the eIF4E to mRNA cap association 23,25 or target eIF4E indirectly like mTOR inhibitors, 31 which repress the downstream phosphorylation of 4E-BP1 and make eIF4E unavailable for initiation of translation. In the present study, we show that eIF4E levels were significantly reduced in a dose-dependent manner in NSCLC cells treated with 4EASO.…”

Section: Discussionmentioning

confidence: 99%

“…When breast carcinoma cancer cell lines were treated with 4Ei1 combined with the drug 5-fluorouracil there was enhanced cytostatic and/or cytotoxic effects compared with each compound alone. 25 One tactic that was employed to decrease eIF4E abundance in breast carcinoma subtypes was with treatments that used short-interfering RNA against eIF4E. 26 eIF4E knockdown led to growth inhibition of breast cancer cell lines and also decreased the expression of the oncogenic proteins, Cyclin D1, Bcl-2 and Bcl-xL.…”

Section: Introductionmentioning

confidence: 99%

Antisense oligonucleotide targeting eukaryotic translation initiation factor 4E reduces growth and enhances chemosensitivity of non-small-cell lung cancer cells

et al. 2015

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Elevated levels of eukaryotic translation initiation factor 4E (eIF4E) enhance translation of many malignancy-related proteins, such as vascular endothelial growth factor (VEGF), c-Myc and osteopontin. In non-small-cell lung cancer (NSCLC), levels of eIF4E are significantly increased compared with normal lung tissue. Here, we used an antisense oligonucleotide (ASO) to inhibit the expression of eIF4E in NSCLC cell lines. eIF4E levels were significantly reduced in a dose-dependent manner in NSCLC cells treated with eIF4E-specific ASO (4EASO) compared with control ASO. Treatment of NSCLC cells with the 4EASO resulted in decreased cap-dependent complex formation, decreased cell proliferation and increased sensitivity to gemcitabine. At the molecular level, repression of eIF4E with ASO resulted in decreased expression of the oncogenic proteins VEGF, c-Myc and osteopontin, whereas expression of β-actin was unaffected. Based on these findings, we conclude that eIF4E-silencing therapy alone or in conjunction with chemotherapy represents a promising approach deserving of further investigation in future NSCLC clinical trials.

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“…Binding protein eIF4E to N(7)-methylated guanosine capped mRNA has been found to be the rate-limiting step governing translation initiation, and therefore represents an attractive target for drug discovery. It has been found that 7-benzyl guanosine monophosphate (7Bn-GMP) is a potent antagonist of (19,20). Recent X-ray crystallographic studies have revealed that the capdependent pocket undergoes a unique structural change in order to accommodate the benzyl group.…”

Section: Disruptors Of 5' Cap Complexmentioning

confidence: 99%

Targeting eukaryotic protein translation in mesothelioma

Kratzke¹

2017

Transl. Lung Cancer Res.

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The default mechanism for protein translation in eukaryotes involves activation of the eIF4 complex at the 5' end of mRNA. This activity is upregulated in cancers, resulting in the expression of a variety of proteins necessary for the development and maintenance of the neoplastic state. Not surprisingly, mesothelioma demonstrates this same reliance on activation of 5' cap mediated translation.Efforts are ongoing to target and exploit our knowledge of this key molecular switch for cancer therapy.Agents targeting the critical eIF4E cap binding protein, disruption of the eIF4 complex, and exploitation for oncolytic virotherapy are some of the important areas of current research in mesothelioma protein translational research.

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Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn7-GMP

Cited by 43 publications

References 42 publications

eIF4E3 acts as a tumor suppressor by utilizing an atypical mode of methyl-7-guanosine cap recognition

eIF4E3 acts as a tumor suppressor by utilizing an atypical mode of methyl-7-guanosine cap recognition

Antisense oligonucleotide targeting eukaryotic translation initiation factor 4E reduces growth and enhances chemosensitivity of non-small-cell lung cancer cells

Targeting eukaryotic protein translation in mesothelioma

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