title: The synergistic inhibition of breast cancer proliferation by combined treatment with 4EGI-1 and MK2206.
abstract: Cap-dependent translation is a potential cancer-related target (oncotarget) due to its critical role in cancer initiation and progression. 4EGI-1, an inhibitor of eIF4E/eIF4G interaction, was discovered by screening chemical libraries of small molecules. 4EGI-1 inhibits cap-dependent translation initiation by impairing the assembly of the eIF4E/eIF4G complex, and therefore is a potential anti-cancer agent. Here, we report that 4EGI-1 also inhibits mTORC1 signaling independent of its inhibitory role on cap-dependent translation initiation. The inhibition of mTORC1 signaling by 4EGI-1 activates Akt due to both abrogation of the negative feedback loops from mTORC1 to PI3K and activation of mTORC2. We further validated that mTORC2 activity is required for 4EGI-1-mediated Akt activation. The activated Akt counteracted the anticancer effects of 4EGI-1. In support of this model, inhibition of Akt potentiates the antitumor activity of 4EGI-1 both in vitro and in a xenograft mouse model in vivo. Our results suggest that a combination of 4EGI-1and Akt inhibitor is a rational approach for the treatment of cancer.
authors.affiliation: a Laboratory of Medical Molecular Biology; Beijing Institute of Biotechnology ; Beijing , P.R. China.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Huang
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Wenjie
authors.initials: W
authors.lastname: Lv
authors.forename: Liu
authors.initials: L
authors.lastname: Hong
authors.forename: Shanhu
authors.initials: S
authors.lastname: Li
authors.forename: Jianguang
authors.initials: J
authors.lastname: Zhou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000627:therapeutic use / Q000633:toxicity*; D006801:Humans; D006835:Hydrazones / Q000627:therapeutic use / Q000633:toxicity*; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000627:therapeutic use / Q000633:toxicity*; D014183:Transplantation, Heterologous
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D006575:Heterocyclic Compounds, 3-Ring; D006835:Hydrazones; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D013844:Thiazoles; C517852:4EGI-1 compound; C087000:EIF4EBP1 protein, human; C548887:MK 2206
keywords: 4EBP1; 4EBP1, eIF4E-binding protein 1; 4EGI-1; AKT; ER stress, endoplasmic reticulum stress; PI3K, phosphatidylinositol 3-kinase; cap-dependent translation; eIF4E; eIF4E, eukaryotic translation initiation factor 4E; eIF4F complex; mTORC1; mTORC1, mammalian target of rapamycin complex 1; mTORC2; mTORC2 mammalian target of rapamycin complex 2; p70S6K, ribosomal p70 S6 kinase