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

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Hsieh TC, Lin CY, Bennett DJ, Wu E, Wu JM

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

PLoS One. 2014 Jun 26;9(6):e101070. doi: 10.1371/journal.pone.0101070. eCollection 2014.

PubMed ID

24968355 [ View in PubMed

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Abstract

BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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 approximately 4 h in control cells to approximately 1 h in NQO2-knockdown cells. The inhibition of AKT by resveratrol was attenuated in NQO2-expressing relative to NQO2-knockdown cells. CONCLUSION/SIGNIFICANCE: Both NQO2 and AKT are targets of resveratrol; NQO2:AKT interaction is a novel physiological regulator of AKT activation/function.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Resveratrol	RAC-alpha serine/threonine-protein kinase	Protein	Humans	Unknown	Inhibitor	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Resveratrol	Investigational	AKT1	207	downregulated	resveratrol results in decreased expression of AKT1 mRNA	14q32.33