Enhance tumor radiosensitivity by intracellular delivery of eukaryotic translation initiation factor 4E binding proteins.

Abstract

PTEN (phosphatase and tensin homologue deleted on chromosome ten)/PI3K (phosphatidylinositol 3-kinase)/Akt/mTOR (mammalian target of rapamycin) signaling pathway, which is commonly dysregulated in a broad array of human malignancies, controls the assembly of eukaryotic translation initiation factor 4F (eIF4F) complex through regulation of eIF4E binding proteins (4E-BPs) phosphorylation. And accumulated data over the past two decades implicated eIF4F complex as one of the promising targets for anticancer therapy. It has been confirmed that the translation initiation of mRNA coding for hypoxia-inducible factor-1α (HIF-1α) and survivin, which had been considered as the two major determinants of tumor radiosensitivity, are both controlled by eIF4F complex. Also, eIF4F complex controls the expression of VEGF and bFGF, the two well-known pro-angiogenic factors involved in developing radioresistance. Therefore eIF4F complex plays a pivotal role in regulation of radiosensitivity. In this article, we postulate that cell-permeable, phosphorylation-defective 4E-BP fusion proteins, which could be prepared by substituting the mTOR recognition motif located in N-terminal of 4E-BPs with protein transduction domain from HIV-1 TAT, HSV-1 VP22 or PTD4, could not only inhibit tumor growth but also enhance tumor response to radiation therapy through disruption of eIF4F complex assembly. In our opinion, the recombinant fusion proteins are superior to mTOR inhibitors for they do not cause immunosuppression, do not lead to Akt activation, and could be easily prepared by prokaryotic expression. If the hypothesis was proved to be practical, the cell-permeable, phosphorylation-defective 4E-BP fusion proteins would be widely used in clinical settings to improve tumor response to radiotherapy in the near future.

• Authors: Shuang Tian, Xiu-Li Li, Mei Shi, Yuan-Qing Yao, Li-Wen Li, Xiao-Yan Xin
• Journal: Medical hypotheses (Med Hypotheses) Vol. 76 Issue 2 Pg. 246-8 (Feb 2011) ISSN: 1532-2777 [Electronic] United States
• PMID: 21050669 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• BIRC5 protein, human
• Eukaryotic Initiation Factor-4E
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Inhibitor of Apoptosis Proteins
• Recombinant Fusion Proteins
• Survivin
• Vascular Endothelial Growth Factor A
• Fibroblast Growth Factor 2
• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Antineoplastic Agents (pharmacology)
• Eukaryotic Initiation Factor-4E (metabolism)
• Fibroblast Growth Factor 2 (metabolism)
• Humans
• Hypoxia
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Inhibitor of Apoptosis Proteins (metabolism)
• Models, Biological
• Neoplasms (radiotherapy, therapy)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Radiation Tolerance
• Recombinant Fusion Proteins (chemistry)
• Survivin
• TOR Serine-Threonine Kinases (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)