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: Magdalena M Bajer, Michael M Kunze, Johanna S Blees, Heidi R Bokesch, Hanyong Chen, Thilo F Brauss, Zigang Dong, Kirk R Gustafson, Ricardo M Biondi, Curtis J Henrich, James B McMahon, Nancy H Colburn, Tobias Schmid, Bernhard Brüne
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 88 Issue 3 Pg. 313-21 (Apr 01 2014) ISSN: 1873-2968 [Electronic] England
• PMID: 24513322 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• 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
• Apoptosis Regulatory Proteins
• Isoflavones
• Multiprotein Complexes
• PDCD4 protein, human
• RNA-Binding Proteins
• MTOR protein, human
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases

Topics

• Apoptosis Regulatory Proteins (metabolism)
• HEK293 Cells
• Humans
• Isoflavones (pharmacology)
• MCF-7 Cells
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• Molecular Docking Simulation
• Multiprotein Complexes (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Biosynthesis (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA-Binding Proteins (metabolism)
• Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)