Targeting the eukaryotic translation initiation factor 4E for cancer therapy

Cancer Growth and Translational Genetics, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Cancer Research (Impact Factor: 9.28). 03/2008; 68(3):631-4. DOI: 10.1158/0008-5472.CAN-07-5635
Source: PubMed

ABSTRACT The eukaryotic translation initiation factor 4E (eIF4E) is frequently overexpressed in human cancers in relation to disease progression and drives cellular transformation, tumorigenesis, and metastatic progression in experimental models. Enhanced eIF4E function results from eIF4E overexpression and/or activation of the ras and phosphatidylinositol 3-kinase/AKT pathways and selectively increases the translation of key mRNAs involved in tumor growth, angiogenesis, and cell survival. Consequently, by simultaneously and selectively reducing the expression of numerous potent growth and survival factors critical for malignancy, targeting eIF4E for inhibition may provide an attractive therapy for many different tumor types. Recent work has now shown the plausibility of therapeutically targeting eIF4E and has resulted in the advance of the first eIF4E-specific therapy to clinical trials. These studies illustrate the increased susceptibility of tumor tissues to eIF4E inhibition and support the notion that the enhanced eIF4E function common to many tumor types may represent an Achilles' heel for cancer.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Elevated protein synthesis is an important feature of many cancer cells and often arises as a consequence of increased signaling flux channeled to eukaryotic initiation factor 4F (eIF4F), the key regulator of the mRNA-ribosome recruitment phase of translation initiation. In many cellular and preclinical models of cancer, eIF4F deregulation results in changes in translational efficiency of specific mRNA classes. Importantly, many of these mRNAs code for proteins that potently regulate critical cellular processes, such as cell growth and proliferation, enhanced cell survival and cell migration that ultimately impinge on several hallmarks of cancer, including increased angiogenesis, deregulated growth control, enhanced cellular survival, epithelial-to-mesenchymal transition, invasion, and metastasis. By being positioned as the molecular nexus downstream of key oncogenic signaling pathways (e.g., Ras, PI3K/AKT/TOR, and MYC), eIF4F serves as a direct link between important steps in cancer development and translation initiation. Identification of mRNAs particularly responsive to elevated eIF4F activity that typifies tumorigenesis underscores the critical role of eIF4F in cancer and raises the exciting possibility of developing new-in-class small molecules targeting translation initiation as antineoplastic agents. Cancer Res; 75(2); 250-63. ©2014 AACR. ©2014 American Association for Cancer Research.
    Cancer Research 01/2015; 75(2):250-263. DOI:10.1158/0008-5472.CAN-14-2789 · 9.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cap dependent translation is mainly regulated at the level of the eukaryotic initiation factor 4E (eIF4E), the activity of which is controlled by phosphorylation and sequestration by its well established regulator, 4E binding protein 1 (4E-BP1). Both eIF4E and 4E-BP1 have been shown to be involved in the malignant progression of multiple human cancers, including colorectal cancer. However, the data on determining the expression of eIF4E, 4E-BP1 and their phosphorylated forms simultaneously in a single patient with colorectal cancer is lacking. Therefore the aim of our study was to explore the roles of these factors in colorectal carcinogenesis by immunohistostaining colorectal tissues (normal, low grade adenoma, high grade adenoma, and adenocarcinoma). Our results showed that the expression levels of eIF4E increased steadily as the cancer progressed from the case of benign dysplasia to an adenocarcinoma; all the while maintaining an unphosphorylated form. On the other hand, total expression levels of 4E-BP1 increased only in the premalignant state of the disease and decreased (but highly phosphorylated or inactivated) or abolished upon malignancy. Taken together, our findings suggest that strong correlations exist between the expression of eIF4E (not p-eIF4E) and tumor grade providing evidence that eIF4E expression plays a pivotal role in the malignant progression of colorectal cancer. Moreover, 4E-BP1 showed a bi-phasic level of expression during carcinogenesis, which is expressed only in hyperplasic or dysplastic tissues as an endogenous tumor suppressor molecule.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ribavirin is an anti-viral drug; however, recent data suggest that it may also be effective in cancer therapy. This study investigated the effect of ribavirin alone or in combination with IFN-α on biological processes: proliferation, apoptosis, and migration of murine (Renca) and human renal carcinoma (RCC) cells (786-0) in vitro. Renca and 786-0 cells were treated with IFN-α, ribavirin, or a combination of IFN-α and ribavirin at varying concentrations. Cell proliferation was evaluated using CCK-8 assay. Induction of apoptosis and distribution of cell cycle were determined by flow cytometry. The migratory capacity of cells was quantified using a transwell migration assay. The toxic effect of these drugs was examined using MTT assay in HEK-293 cells. ELISA was used to measure IL-10 and TGF-β content in the culture supernatants. Our results showed that both ribavirin alone and in combination with IFN-α could significantly inhibit the cell proliferation and arrest the cell cycle progress at the G2/M phase. These treatments also inhibited cell migration and IL-10 production, in a concentration-dependent manner, in 786-0 and Renca cells. Moreover, they significantly induced apoptosis of RCC cells and increased TGF-β production in concentration-dependent manner. No significant toxic effect was observed in HEK-293 cells. We also found that the effect of combined treatment was more pronounced than that of ribavirin or IFN-α alone. However, the combined effect of the two drugs was not synergistic. Our findings suggest that ribavirin can negatively affect biological processes of RCC cells. This agent might become a new candidate for the treatment of RCC in the clinical setting.
    Cancer Cell International 09/2014; 14:63. DOI:10.1186/1475-2867-14-63 · 1.99 Impact Factor



Similar Publications