Inhibition of Ovarian Cancer Growth by a Tumor-Targeting Peptide That Binds Eukaryotic Translation Initiation Factor 4E

Abstract

Purpose: A critical step of protein synthesis involves the liberation of the mRNA capbinding translation initiation factor eIF4E from 4EBP inhibitory binding proteins, and its engagement to the scaffolding protein eIF4G. eIF4E is a candidate target for cancer therapy because it is overexpressed or activated in many types of tumors and has tumorigenic properties. Our aim was to design and evaluate 4EBP-based peptides for their antitumor activity in ovarian cancer. Experimental Design: The ability of peptides to bind and inhibit eIF4E was determined by immunoprecipitation and by assaying cap-dependent reporter synthesis. To target ovarian tumors, the lead candidate 4EBP peptide was fused to an analog of gonadotropin-releasing hormone (GnRH). Cellular uptake of peptide, and effects on cell viability and cell death were determined. The antitumor activity of fusion peptide was evaluated in female nude mice bearing i.p. ovarian tumor xenografts. Results: 4EBP-based peptides bound eIF4E, prevented eIF4E from binding eIF4G, and inhibited cap-dependent translation. GnRH agonist-4EBP fusion peptide was taken up by, and inhibited the growth of, GnRH receptor-expressing tumor cells, but not receptornegative cells. Intraperitoneal tumor burden was significantly smaller in mice treated with fusion peptide than in mice treated with saline (P < 0.001). Ascites was also reduced in peptide-treated mice. Significant cytotoxic effects to host tissues were not observed. On the other hand, treatment with GnRH agonist alone did not inhibit tumor growth or ascites. Conclusion: Because ovarian cancer is rarely cured by conventional chemotherapies, GnRH-4EBP fusion peptide may be of therapeutic potential for treatment of this disease.

Targeting the eIF4A RNA helicase as an anti-neoplastic approach

“…Several of these show micromolar potency and have proven to be useful tool compounds for probing the role of deregulated translation in the tumorigenic process ex vivo whereas others are more potent and show in vivo efficacy in pre-clinical cancer models. As an example, proof-of-concept for targeting eIF4E/eIF4G interaction in vivo as an anti-cancer approach has been demonstrated using a 4E-BP1-derived peptide fused to an agonist of the gonadotropin-releasing hormone (GnRH), whose corresponding receptor is expressed in 80% of epithelial ovarian cancers [43]. Remarkably, the fusion peptide was able to abrogate eIF4E/eIF4G association, inhibit translation in a tumor cell-specific manner, and reduce tumor burden in a xenograft mouse model of epithelial ovarian cancer [43].…”

“…As an example, proof-of-concept for targeting eIF4E/eIF4G interaction in vivo as an anti-cancer approach has been demonstrated using a 4E-BP1-derived peptide fused to an agonist of the gonadotropin-releasing hormone (GnRH), whose corresponding receptor is expressed in 80% of epithelial ovarian cancers [43]. Remarkably, the fusion peptide was able to abrogate eIF4E/eIF4G association, inhibit translation in a tumor cell-specific manner, and reduce tumor burden in a xenograft mouse model of epithelial ovarian cancer [43]. In addition, small molecule inhibitors of eIF4E/eIF4G interaction are capable of re-sensitizing chemoresistant lymphomas to doxorubicin in the murine Eμ-Myc lymphoma model [44].…”

Spatial and temporal translational control of germ cell mRNAs mediated by the eIF4E isoform IFE-1

“…Dysregulation of these processes is associated with human pathologies including infertility, birth defects and cancers (Graff et al, 2008;Song and Lu, 2011). Clinical studies have shown that the eukaryotic translation initiation factor eIF4E is overexpressed in multiple cancers including ovarian, esophageal, breast, thyroid and prostate (Furic et al, 2010;Ko et al, 2009;Kouvaraki et al, 2011;Salehi and Mashayekhi, 2006). Its overexpression upregulates the translation of mRNAs for cell cycle, growth and reactive oxygen species (ROS) regulatory proteins (De Benedetti and Graff, 2004;De Benedetti and Rhoads, 1990;Rosenwald, 2004;Rosenwald et al, 1993), leading to the cancer phenotype.…”

Inhibitions of mTORC1 and 4EBP-1 are key events orchestrated by Rottlerin in SK-Mel-28 cell killing

“…inhibition of cap-dependent protein translation via mTORC1/4EBP-1 inhibition. Recently, eIF4F inactivation is emerging as a promising approach for anti-cancer intervention [29][30][31], which could be particularly important in those cancer cells where the canonical modes of cell death are expected to be defective. The current results also emphasized the versatility of Rottlerin as anticancer drug in a variety of cellular models, which greatly differ from each other in terms of genetic/biochemical profile and chemosensitivity.…”