title: Components of the eIF4F complex are potential therapeutic targets for malignant peripheral nerve sheath tumors and vestibular schwannomas.
abstract: The eukaryotic initiation factor 4F (eIF4F) complex plays a pivotal role in protein translation initiation; however, its importance in malignant and benign Schwann cell tumors has not been explored, and whether blocking eIF4F function is effective for treating these tumors is not known.
  
  
  
  Immunostaining was performed on human malignant peripheral nerve sheath tumors (MPNSTs) and vestibular schwannomas (VSs) for eIF4F components. The role of eIF4A and eIF4E in cell growth was assessed by RNA interference. Various natural compounds were screened for their growth-inhibitory activity. Flow cytometry and Western blotting were performed to characterize the action of silvestrol, and its antitumor activity was verified in orthotopic mouse models.
  
  
  
  MPNSTs and VSs frequently overexpressed eIF4A, eIF4E, and/or eIF4G. Depletion of eIF4A1, eIF4A2, and eIF4E substantially reduced MPNST cell growth. From screening a panel of plant-derived compounds, the eIF4A inhibitor silvestrol was identified as a leading agent with nanomolar IC50 values in MPNST and VS cells. Silvestrol induced G2/M arrest in both NF1-deficient and NF1-expressing MPNST cells and primary VS cells. Silvestrol consistently decreased the levels of multiple cyclins, Aurora A, and mitogenic kinases AKT and ERKs. Silvestrol treatment dramatically suppressed tumor growth in mouse models for NF1(-/-) MPNST and Nf2(-/-) schwannoma. This decreased tumor growth was accompanied by elevated phospho-histone H3 and TUNEL labeling, consistent with G2/M arrest and apoptosis in silvestrol-treated tumor cells.
  
  
  
  The eIF4F complex is a potential therapeutic target in MPNSTs and VS, and silvestrol may be a promising agent for treating these tumors.
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, E.M.A, J.H., L.-S.C.); Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, B.M.M, A.C.M, D.B.W, L.-S.C.); Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio (R.S., L.-S.C.); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio (L.P., Y.R., A.D.K.).
authors.forename: Janet L
authors.initials: JL
authors.lastname: Oblinger
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, E.M.A, J.H., L.-S.C.); Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, B.M.M, A.C.M, D.B.W, L.-S.C.); Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio (R.S., L.-S.C.); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio (L.P., Y.R., A.D.K.).
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Burns
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, E.M.A, J.H., L.-S.C.); Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, B.M.M, A.C.M, D.B.W, L.-S.C.); Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio (R.S., L.-S.C.); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio (L.P., Y.R., A.D.K.).
authors.forename: Elena M
authors.initials: EM
authors.lastname: Akhmametyeva
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, E.M.A, J.H., L.-S.C.); Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, B.M.M, A.C.M, D.B.W, L.-S.C.); Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio (R.S., L.-S.C.); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio (L.P., Y.R., A.D.K.).
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, E.M.A, J.H., L.-S.C.); Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, B.M.M, A.C.M, D.B.W, L.-S.C.); Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio (R.S., L.-S.C.); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio (L.P., Y.R., A.D.K.).
authors.forename: Li
authors.initials: L
authors.lastname: Pan
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, E.M.A, J.H., L.-S.C.); Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, B.M.M, A.C.M, D.B.W, L.-S.C.); Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio (R.S., L.-S.C.); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio (L.P., Y.R., A.D.K.).
authors.forename: Yulin
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, E.M.A, J.H., L.-S.C.); Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, B.M.M, A.C.M, D.B.W, L.-S.C.); Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio (R.S., L.-S.C.); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio (L.P., Y.R., A.D.K.).
authors.forename: Rulong
authors.initials: R
authors.lastname: Shen
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, E.M.A, J.H., L.-S.C.); Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, B.M.M, A.C.M, D.B.W, L.-S.C.); Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio (R.S., L.-S.C.); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio (L.P., Y.R., A.D.K.).
authors.forename: Beth
authors.initials: B
authors.lastname: Miles-Markley
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, E.M.A, J.H., L.-S.C.); Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, B.M.M, A.C.M, D.B.W, L.-S.C.); Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio (R.S., L.-S.C.); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio (L.P., Y.R., A.D.K.).
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Moberly
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, E.M.A, J.H., L.-S.C.); Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, B.M.M, A.C.M, D.B.W, L.-S.C.); Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio (R.S., L.-S.C.); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio (L.P., Y.R., A.D.K.).
authors.forename: A Douglas
authors.initials: AD
authors.lastname: Kinghorn
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, E.M.A, J.H., L.-S.C.); Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, B.M.M, A.C.M, D.B.W, L.-S.C.); Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio (R.S., L.-S.C.); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio (L.P., Y.R., A.D.K.).
authors.forename: D Bradley
authors.initials: DB
authors.lastname: Welling
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, E.M.A, J.H., L.-S.C.); Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio (J.L.O, S.S.B, B.M.M, A.C.M, D.B.W, L.-S.C.); Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio (R.S., L.-S.C.); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio (L.P., Y.R., A.D.K.) lchang@chi.osu.edu.
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Chang
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D049109:Cell Proliferation; D039601:Eukaryotic Initiation Factor-4A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors / Q000378:metabolism*; D039562:Eukaryotic Initiation Factor-4F / Q000037:antagonists & inhibitors / Q000378:metabolism*; D039603:Eukaryotic Initiation Factor-4G / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009442:Neurilemmoma / Q000378:metabolism* / Q000473:pathology; D009464:Neuroma, Acoustic / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D039561:Eukaryotic Initiation Factor-4E; D039562:Eukaryotic Initiation Factor-4F; D039603:Eukaryotic Initiation Factor-4G; D034741:RNA, Small Interfering; D039601:Eukaryotic Initiation Factor-4A
keywords: eIF4F complex; malignant peripheral nerve sheath tumor (MPNST); orthotopic mouse models; silvestrol; vestibular schwannoma (VS)