Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity

      Graff et al., The Journal of Clinical Investigation 117:2638-2648. (2007)  

Speaker: 魏麗勳                           Time: 13:10~14:00, Nov. 28, 2007

Commentator: 吳梨華老師                   Place: Room 601

Abstract

Tumorigenesis involves overproduction of many oncoproteins, such as those for cell proliferation, angiogenesis and anti-apoptosis. Compared with housekeeping proteins, synthesis of the oncoproteins is very sensitive to the level of cap-dependent translation machinery, of which the rate-limiting factor is eukaryotic translation initiation factor 4E (eIF4E). Under normal cellular condition, eIF4E is sequestered by eIF4E binding proteins (4E-BPs), so eIF4E availability for translation is limited (1). During tumorigenesis, abnormal activation of the PI3 kinase/mTOR pathway results inphosphorylation of 4E-BPs, release of eIF4E and subsequent increase of translation efficiency. In addition, overexpression of eIF4E has been detected in many cancers and shown to enhance cell transformation (2). Considering that reduction of eIF4E can decrease production of oncoproteins, it may be a feasible strategy to target eIF4E for cancer therapy. In this paper, the authors designed eIF4E-specific antisense oligonucleotides (ASOs) with second-generation modification to increase nuclease resistance and tissue stability (3). The ASOs reduced expression of eIF4E and eIF4E-regulated oncoproteins, induced apoptosis of tumor cells, and blocked endothelial cell tube formation in vitro. The most exciting result was that intravenous ASO administration inhibited growth of tumor xenografts in vivo. Notably, the potential toxicity of the ASOs was seemingly low, since they had no significant effect on global protein translation , body weight, organ weight and liver transaminase levels. Although several issues need to be further concerned, this study has encouraged clinical trials using eIF4E-targeted ASOs as therapeutic agents to treat human cancers.

References:

(1) Thomas E. Dever .Gene-Specific Regulation by General Translation Factors. Cell 108: 545-556 (2002)

(2)Arrigo De Benedetti and Jeremy R Graff. eIF-4E expression and its role in malignancies and metastases. Oncogene. 23: 3189–3199 (2004)

(3)Nicholas M Dean and C Frank Bennett. Antisense oligonucleotide-based therapeutics for cancer. Oncogene. 22: 9087–9096 (2003)