Abstract
BackgroundAKT 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 FindingsIn 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.Conclusion/SignificanceBoth NQO2 and AKT are targets of resveratrol; NQO2:AKT interaction is a novel physiological regulator of AKT activation/function.
Highlights
AKT, a serine-threonine kinase that is involved in a variety of cellular processes including cell survival, proliferation, metabolism, and response to inflammatory agents [1,2,3,4], is aberrantly activated in correlation with oncogenic transformation and tumor growth
Since we found that NQO2-knockdown cells showed an accompanying increase in AKT activity [19], we consider that NQO2 could decrease AKT activity through its direct binding to AKT and in addition, possibly by forming a complex with resveratrol
Evidence that interaction occurs between NQO2 and AKT Previously, we reported an increase in AKT activity in NQO2 knockdown CWR22Rv1 cells [19], raising the possibility that NQO2 might form a complex with AKT and providing a mechanism that may sequester AKT and prevent its functional activation
Summary
AKT, a serine-threonine kinase that is involved in a variety of cellular processes including cell survival, proliferation, metabolism, and response to inflammatory agents [1,2,3,4], is aberrantly activated in correlation with oncogenic transformation and tumor growth. Epidemiologic studies demonstrate an association between consumption of diet rich in fruits and vegetables with reduced risk of developing many cancer types; dietary grape polyphenol resveratrol has been shown to inhibit AKT activity [13,14,15,16,17]. It is not known how resveratrol controls AKT, in the context of its reported anti-CaP activity. We recently reported that quinone reductase 2 (NQO2) inhibited AKT activity, by unknown mechanisms
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
