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Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells
Published on: May 1, 2020
Differential Regulation of the Melanoma Proteome by eIF4A1 and eIF4E
Cailin E Joyce1,2,3, Adrienne G Yanez1,2,3, Akihiro Mori4,5,6
1Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Abstract:
Small molecules and antisense oligonucleotides that inhibit the translation initiation factors eIF4A1 and eIF4E have been explored as broad-based therapeutic agents for cancer treatment, based on the frequent upregulation of these two subunits of the eIF4F cap-binding complex in many cancer cells. Here, we provide support for these therapeutic approaches with mechanistic studies of eIF4F-driven tumor progression in a preclinical model of melanoma. Silencing eIF4A1 or eIF4E decreases melanoma proliferation and invasion. There were common effects on the level of cell-cycle proteins that could explain the antiproliferative effects in vitro Using clinical specimens, we correlate the common cell-cycle targets of eIF4A1 and eIF4E with patient survival. Finally, comparative proteomic and transcriptomic analyses reveal extensive mechanistic divergence in response to eIF4A1 or eIF4E silencing. Current models indicate that eIF4A1 and eIF4E function together through the 5'UTR to increase translation of oncogenes. In contrast, our data demonstrate that the common effects of eIF4A1 and eIF4E on translation are mediated by the coding region and 3'UTR. Moreover, their divergent effects occur through the 5'UTR. Overall, our work shows that it will be important to evaluate subunit-specific inhibitors of eIF4F in different disease contexts to fully understand their anticancer actions. Cancer Res; 77(3); 613-22. ©2016 AACR.
Insights
Inhibiting translation factors eIF4A1 and eIF4E slows melanoma growth and invasion. Their anticancer effects differ mechanistically, highlighting the need for subunit-specific inhibitors in cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Translation initiation factors eukaryotic initiation factor 4A1 (eIF4A1) and eukaryotic initiation factor 4E (eIF4E) are subunits of the eIF4F complex.
- Upregulation of eIF4F subunits is common in various cancer cells, making them potential therapeutic targets.
- Targeting eIF4F subunits is explored for broad-based cancer treatment strategies.
Purpose of the Study:
- To investigate the mechanistic roles of eIF4A1 and eIF4E in melanoma progression.
- To determine the common and divergent effects of eIF4A1 and eIF4E inhibition on cancer cells.
- To correlate eIF4A1 and eIF4E targets with patient survival in melanoma.
Main Methods:
- Preclinical melanoma models were used to study the effects of silencing eIF4A1 or eIF4E.
- Cell-cycle protein levels were analyzed to understand antiproliferative effects.
- Clinical specimens were used to correlate eIF4A1/eIF4E targets with patient survival.
- Comparative proteomic and transcriptomic analyses were performed to reveal mechanistic differences.
Main Results:
- Silencing eIF4A1 or eIF4E reduced melanoma proliferation and invasion.
- Common effects on cell-cycle proteins were observed, explaining antiproliferative impacts.
- Proteomic and transcriptomic analyses revealed significant mechanistic divergence between eIF4A1 and eIF4E inhibition.
- Contrary to current models, common translational effects involved coding regions and 3'UTRs, while divergent effects involved 5'UTRs.
Conclusions:
- eIF4A1 and eIF4E play crucial roles in melanoma progression, and their inhibition shows therapeutic potential.
- The common antiproliferative effects are linked to cell-cycle regulation.
- Mechanistic studies reveal distinct roles for eIF4A1 and eIF4E in translation, challenging existing models.
- Evaluating subunit-specific eIF4F inhibitors is essential for understanding and optimizing anticancer strategies in diverse disease contexts.
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