Vitamin e facilitates the inactivation of the kinase akt by the phosphatase PHLPP1
Journal
Science Signaling
Journal Volume
6
Journal Issue
267
Date Issued
2013-03
Author(s)
Huang, P.-H.
Chuang, H.-C.
Chou, C.-C.
Wang, H.
Lee, S.-L.
Yang, H.-C.
Kapuriya, N.
Wang, D.
Kulp, S.K.
Chen, C.-S.
Abstract
Vitamin E is a fat-soluble vitamin with antioxidant properties. Tocopherols are the predominant form of vitamin E found in the diet and in supplements and have garnered interest for their potential cancer therapeutic and preventive effects, such as the dephosphorylation of Akt, a serine/threonine kinase with a pivotal role in cell growth, survival, and metabolism. Dephosphorylation of Akt at Ser473 substantially reduces its catalytic activity and inhibits downstream signaling. We found that the mechanism by which α-tocopherol and γ-tocopherol facilitate this site-specific dephosphorylation of Akt was mediated through the pleckstrin homology (PH) domain-dependent recruitment of Akt and PHLPP1 (PH domain leucine-rich repeat protein phosphatase, isoform 1) to the plasma membrane. We structurally optimized these tocopherols to obtain derivatives with greater in vitro potency and in vivo tumor-suppressive activity in two prostate xenograft tumor models. Binding affinities for the PH domains of Akt and PHLPP1 were greater than for other PH domain-containing proteins, which may underlie the preferential recruitment of these proteins to membranes containing tocopherols. Molecular modeling revealed the structural determinants of the interaction with the PH domain of Akt that may inform strategies for continued structural optimization. By describing a mechanism by which tocopherols facilitate the dephosphorylation of Akt at Ser473, we provide insights into the mode of antitumor action of tocopherols and a rationale for the translational development of tocopherols into novel PH domain-targeted Akt inhibitors.
Other Subjects
alpha tocopherol; alpha VE5; beta VE5; gamma tocopherol; ligand; mammalian target of rapamycin complex 2; PH domain leucine rich repeat protein phosphatase; phosphoprotein phosphatase; pleckstrin; protein kinase B; tocopherol derivative; unclassified drug; enzyme inhibitor; gamma tocopherol; nuclear protein; PHLPP1 protein, human; phosphoprotein phosphatase; protein kinase B; serine; animal cell; animal experiment; animal model; antineoplastic activity; antiproliferative activity; apoptosis; article; binding affinity; cancer inhibition; cell membrane; cell proliferation; cell viability; controlled study; drug cytotoxicity; drug potency; enzyme inactivation; hydrogen bond; immunocytochemistry; in vitro study; in vivo study; male; molecular model; mouse; nonhuman; priority journal; process optimization; prostate cancer; protein dephosphorylation; protein interaction; protein structure; sequence homology; site directed mutagenesis; tumor xenograft; Western blotting; animal; confocal microscopy; drug effect; drug screening; genetics; human; metabolism; nude mouse; phosphorylation; protein binding; RNA interference; signal transduction; tumor cell line; alpha-Tocopherol; Animals; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Membrane; Enzyme Inhibitors; gamma-Tocopherol; Humans; Male; Mice; Mice, Nude; Microscopy, Confocal; Nuclear Proteins; Phosphoprotein Phosphatases; Phosphorylation; Protein Binding; Proto-Oncogene Proteins c-akt; RNA Interference; Serine; Signal Transduction; Vitamin E; Xenograft Model Antitumor Assays
Type
journal article