Biochemical and cellular evidence demonstrating AKT-1 as a binding partner for resveratrol targeting protein NQO2

AKT plays an important role in the control of cell proliferation and survival. Aberrant activation of AKT frequently occurs in human cancers making it an attractive drug targets and leading to the synthesis of numerous AKT inhibitors as therapeutic candidates. Less is known regarding proteins that c...

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Bibliographic Details
Published in:PloS one 2014-06, Vol.9 (6), p.e101070-e101070
Main Authors: Hsieh, Tze-chen, Lin, Chia-Yi, Bennett, Dylan John, Wu, Erxi, Wu, Joseph M
Format: Article
Language:English
Subjects:
Aberration
Activation
Affinity
Affinity chromatography
AKT protein
AKT1 protein
Apoptosis
Asparagine
Binding
Biochemistry
Biology and Life Sciences
Cancer
Carrier Proteins - metabolism
Cell Line
Cell proliferation
Cell survival
Chemical properties
Chromatography
Clonal deletion
Enzyme Activation
Enzymes
Gene Expression
Gene Knockdown Techniques
Health aspects
Histidine
Homology
Humans
Hydrogen Bonding
Inhibition
Kinases
Modelling
Models, Molecular
Molecular biology
Molecular modelling
mRNA
Phosphorylation
Pleckstrin
Prostate
Protein Binding
Protein Conformation
Protein Stability
Protein Transport
Proteins
Proto-Oncogene Proteins c-akt - chemistry
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - metabolism
Quinone
Quinone Reductases - chemistry
Quinone Reductases - genetics
Quinone Reductases - metabolism
Quinones
Reductase
Resveratrol
RNA
RNA Stability
Stilbenes - chemistry
Stilbenes - metabolism
Tumors
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Summary:AKT plays an important role in the control of cell proliferation and survival. Aberrant activation of AKT frequently occurs in human cancers making it an attractive drug targets and leading to the synthesis of numerous AKT inhibitors as therapeutic candidates. Less is known regarding proteins that control AKT. We recently reported that quinone reductase 2 (NQO2) inhibited AKT activity, by unknown mechanisms. In this study, molecular modeling was used to query interaction between NQO2 and AKT. We found that pleckstrin homology (PH) and kinase domains of AKT bind to chains A and B of NQO2. Pull-down and deletion assays revealed that PH domain of AKT is essential for interaction with NQO2. Modeling analysis further revealed that kinase domain of AKT binds NQO2 in the vicinity of asparagine 161 located in the resveratrol-binding domain of NQO2. In studies to test whether exposure to resveratrol potentiates or diminishes AKT binding to NQO2, we showed that pre-binding by resveratrol in wild type but not histidine-161 (N161H) mutant NQO2 significantly affected this interaction. To obtain information on interplay between resveratrol and AKT, resveratrol affinity chromatography was performed. AKT binds with high affinity to the column suggesting that it is a target of resveratrol. The half-life of AKT mRNA decreased from ∼4 h in control cells to ∼1 h in NQO2-knockdown cells. The inhibition of AKT by resveratrol was attenuated in NQO2-expressing relative to NQO2-knockdown cells. Both NQO2 and AKT are targets of resveratrol; NQO2:AKT interaction is a novel physiological regulator of AKT activation/function.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0101070