Song Yi Ko1, Huifang Guo, Nicolas Barengo, Honami Naora. 1. Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, and Cancer Biology Program, Graduate School of Biomedical Sciences, University of Texas Health Sciences Center, Houston, Texas, USA.
Abstract
PURPOSE: A critical step of protein synthesis involves the liberation of the mRNA cap-binding 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 receptor-negative 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.
PURPOSE: A critical step of protein synthesis involves the liberation of the mRNA cap-binding 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 receptor-negative 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.
Authors: Tanasa S Osborne; Ling Ren; John H Healey; Lauren Q Shapiro; Alexander J Chou; Richard G Gorlick; Stephen M Hewitt; Chand Khanna Journal: J Pediatr Hematol Oncol Date: 2011-10 Impact factor: 1.289
Authors: S Aggarwal; M W Ndinguri; R Solipuram; N Wakamatsu; R P Hammer; D Ingram; W Hansel Journal: Int J Cancer Date: 2011-07-20 Impact factor: 7.396
Authors: S C Thumma; B A Jacobson; M R Patel; B W Konicek; M J Franklin; J Jay-Dixon; A Sadiq; A De; J R Graff; R A Kratzke Journal: Cancer Gene Ther Date: 2015-07-31 Impact factor: 5.987