PUBLICATION
Non-Toxic Chemical Interdiction of the Epithelial-to-Mesenchymal Transition by Targeting Cap-dependent Translation
- Authors
- Ghosh, B., Benyumov, A.O., Ghosh, P., Jia, Y., Avdulov, S., Dahlberg, P.S., Peterson, M., Smith, K., Polunovsky, V.A., Bitterman, P.B., and Wagner, C.R.
- ID
- ZDB-PUB-090413-4
- Date
- 2009
- Source
- ACS Chemical Biology 4(5): 367-377 (Journal)
- Registered Authors
- Benyumov, Alexey O.
- Keywords
- none
- MeSH Terms
-
- Amides/chemical synthesis
- Amides/chemistry
- Amides/pharmacology
- Animals
- Base Sequence
- Drug Delivery Systems*
- Embryo, Nonmammalian/embryology
- Epithelium/embryology*
- Eukaryotic Initiation Factor-4E/antagonists & inhibitors
- Humans
- Inhibitory Concentration 50
- Mesoderm/embryology*
- Molecular Sequence Data
- Neoplasms/metabolism
- Nuclear Cap-Binding Protein Complex/antagonists & inhibitors*
- Nuclear Cap-Binding Protein Complex/metabolism*
- Phosphoric Acids/chemical synthesis
- Phosphoric Acids/chemistry
- Phosphoric Acids/pharmacology
- Reverse Transcriptase Polymerase Chain Reaction
- Zebrafish/embryology*
- PubMed
- 19351181 Full text @ ACS Chem. Biol.
Citation
Ghosh, B., Benyumov, A.O., Ghosh, P., Jia, Y., Avdulov, S., Dahlberg, P.S., Peterson, M., Smith, K., Polunovsky, V.A., Bitterman, P.B., and Wagner, C.R. (2009) Non-Toxic Chemical Interdiction of the Epithelial-to-Mesenchymal Transition by Targeting Cap-dependent Translation. ACS Chemical Biology. 4(5):367-377.
Abstract
Normal growth and development depends upon high fidelity regulation of cap-dependent translation initiation; a process that is usurped and redirected in cancer to mediate acquisition of malignant properties. The epithelial-to-mesenchymal transition (EMT) is a key translationally-regulated step in the development of epithelial cancers as well as pathological tissue fibrosis (1-5). To date, no compounds targeting EMT have been developed. Here we report the synthesis of a novel class of Histidine Triad Nucleotide Binding Protein (HINT)-dependent pronucleotides that interdict EMT by negatively regulating the association of eIF4E with the mRNA cap. Compound eIF4E inhibitor-1 (4Ei-1) potently inhibited cap-dependent translation in a dose-dependent manner in zebrafish embryos without causing developmental abnormalities; and prevented eIF4E from triggering EMT in zebrafish ectoderm explants without toxicity. Metabolism studies with whole cell lysates demonstrated that the prodrug was rapidly converted into 7-Bn-GMP. Thus we have successfully developed the first non-toxic small molecule able to inhibit EMT, a key process in the development of epithelial cancer and tissue fibrosis by targeting the interaction of eIF4E with the mRNA cap; and demonstrate the tractability of zebrafish as a model organism for studying agents that modulate EMT. Our work provides strong motivation for the continued development of compounds designed to normalize cap-dependent translation as novel chemo-preventive agents and therapeutics for cancer and fibrosis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping