title: Characterization of pomiferin triacetate as a novel mTOR and translation inhibitor.
abstract: Deregulation of the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR)-70kDa ribosomal protein S6 kinase 1 (p70(S6K)) pathway is commonly observed in many tumors. This pathway controls proliferation, survival, and translation, and its overactivation is associated with poor prognosis for tumor-associated survival. Current efforts focus on the development of novel inhibitors of this pathway. In a cell-based high-throughput screening assay of 15,272 pure natural compounds, we identified pomiferin triacetate as a potent stabilizer of the tumor suppressor programmed cell death 4 (Pdcd4). Mechanistically, pomiferin triacetate appeared as a general inhibitor of the PI3K-Akt-mTOR-p70(S6K) cascade. Interference with this pathway occurred downstream of Akt but upstream of p70(S6K). Specifically, mTOR kinase emerged as the molecular target of pomiferin triacetate, with similar activities against mTOR complexes 1 and 2. In an in vitro mTOR kinase assay pomiferin triacetate dose-dependently inhibited mTOR with an IC50 of 6.2 μM. Molecular docking studies supported the interaction of the inhibitor with the catalytic site of mTOR. Importantly, pomiferin triacetate appeared to be highly selective for mTOR compared to a panel of 17 lipid and 50 protein kinases tested. As a consequence of the mTOR inhibition, pomiferin triacetate efficiently attenuated translation. In summary, pomiferin triacetate emerged as a novel and highly specific mTOR inhibitor with strong translation inhibitory effects. Thus, it might be an interesting lead structure for the development of mTOR- and translation-targeted anti-tumor therapies.
authors: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors: Magdalena M
authors: MM
authors: Bajer
authors: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors: Michael M
authors: MM
authors: Kunze
authors: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors: Johanna S
authors: JS
authors: Blees
authors: Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors: Heidi R
authors: HR
authors: Bokesch
authors: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors: Hanyong
authors: H
authors: Chen
authors: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors: Thilo F
authors: TF
authors: Brauss
authors: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors: Zigang
authors: Z
authors: Dong
authors: Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
authors: Kirk R
authors: KR
authors: Gustafson
authors: Research Group PhosphoSites, Department of Internal Medicine I, University Clinic, 60590 Frankfurt, Germany.
authors: Ricardo M
authors: RM
authors: Biondi
authors: Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors: Curtis J
authors: CJ
authors: Henrich
authors: Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
authors: James B
authors: JB
authors: McMahon
authors: Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
authors: Nancy H
authors: NH
authors: Colburn
authors: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany. Electronic address: t.schmid@biochem.uni-frankfurt.de.
authors: Tobias
authors: T
authors: Schmid
authors: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors: Bernhard
authors: B
authors: Brüne
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D062105:Molecular Docking Simulation; D046912:Multiprotein Complexes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D007529:Isoflavones; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016601:RNA-Binding Proteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C588417:4-(5-acetyloxy-8,8-dimethyl-6-(3-methylbut-2-en-1-yl)-4-oxo-4,8-dihydropyrano(2,3-f)chromen-3-yl)-1,2-phenylene diacetate; C114487:PDCD4 protein, human; C546842:MTOR protein, human
keywords: Mammalian target of rapamycin; Natural product; Pomiferin triacetate; Translation