Abstract IA23: eIF4E as anti-cancer target

Abstract

Abstract The interaction of the cap-binding protein eIF4E with eIF4G is central for recruiting the small ribosomal subunit to the 5' end of mRNA. This interaction is regulated by the competitive interaction with the 4E-binding proteins (4E-BPs). Genome analyses have shown that mRNAs coding for proto-oncogenes, transcription factors, translation factors, growth factors and their receptors have statistically long 5' UTRs with large negative free energies estimated with mfold. Translation of these genes thus, depends heavily on an efficient translation-initiation machinery. This is in contrast to 5' TOP mRNAs and highly expressed genes with expression controlled at the transcription level that have small negative free estimated with mfold. Consistently, overexpression of 4E-BP1 has been shown to suppress tumor growth in mouse xenografts. In a high-throughput screen of compound libraries we discovered a small molecule that mimics the action of 4E-BP1 by displacing eIF4G from eIF4E. Surprisingly, the compound does not displace 4E-BP1 but rather stabilizes its binding both in vitro and in vivo. To understand this effect we have solved crystal structures of complexes between eIF4E and several inhibitor analogs. In addition, we determined the structure of eIF4E in complex with a long fragment of 4E-BP1. These data revealed the dual mechanism of the compound displacing the tumor promoter eIF4G while stabilizing the tumor suppressor 4E-BP1. Furthermore, we investigated the activities of 4EGI-1 aggressive breast cancer cells that have properties of cancer stem cells and find that the compound specifically suppresses the aggressive properties of these cancer cells. In addition, we discovered that eIF4E is transcriptionally upregulated in hypoxia as it promoter contains hypoxia response elements utilized by Hif1a. Finally, we tested 4EGI-1 against a panel of ~1000 cancer cell lines and tested the global impact on Jurkat cells in a proteomics approach. Citation Format: Gerhard Wagner, Evangelos Papadopoulos, Tingfang Yi, Melissa Leger-Abraham, Naotaka Sekiyama. eIF4E as anti-cancer target. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA23.