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Sci. Signal., 19 March 2013
Vol. 6, Issue 267, p. ra19
[DOI: 10.1126/scisignal.2003816]

RESEARCH ARTICLES

Vitamin E Facilitates the Inactivation of the Kinase Akt by the Phosphatase PHLPP1

Po-Hsien Huang1,2*, Hsiao-Ching Chuang1*, Chih-Chien Chou1, Huiling Wang1,3, Su-Lin Lee1, Hsiao-Ching Yang4, Hao-Chieh Chiu1{dagger}, Naval Kapuriya1{ddagger}, Dasheng Wang1, Samuel K. Kulp1, and Ching-Shih Chen1,2§

1 Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
2 Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan 701, Taiwan.
3 Department of Chemical Biology, School of Pharmaceutical Science, Peking University, Health Science Center, Beijing 100191, China .
4 Department of Chemistry, Fu-Jen Catholic University, Xinzhuang District, New Taipei City 24205, Taiwan.

* These authors contributed equally to this work.

{dagger} Present address: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.

{ddagger} Present address: M. & N. Virani Science College, Division of Pharmaceutical and Organic Chemistry, Saurashtra University, Rajkot 360005, Gujarat, India.

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 {gamma}-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.

§ Corresponding author. E-mail: chen.844{at}osu.edu

Citation: P.-H. Huang, H.-C. Chuang, C.-C. Chou, H. Wang, S.-L. Lee, H.-C. Yang, H.-C. Chiu, N. Kapuriya, D. Wang, S. K. Kulp, C.-S. Chen, Vitamin E Facilitates the Inactivation of the Kinase Akt by the Phosphatase PHLPP1. Sci. Signal. 6, ra19 (2013).

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