Modulation of Pro-survival Akt/Protein Kinase B and ERK1/2 Signaling Cascades by Quercetin and Its in Vivo Metabolites Underlie Their Action on Neuronal Viability

• Published in: The Journal of biological chemistry 2003-09, Vol.278 (37), p.34783-34793
• Main Authors: Spencer, Jeremy P.E., Rice-Evans, Catherine, Williams, Robert J.
• Format: Article
• Language: English
• Subjects: Animals; Cell Survival - drug effects; Cells, Cultured; Cerebral Cortex - physiology; Kinetics; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Neurons - cytology; Neurons - drug effects; Neurons - physiology; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Quercetin - pharmacokinetics; Quercetin - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M305063200

Much recent interest has focused on the potential of flavonoids to interact with intracellular signaling pathways such as with the mitogen-activated protein kinase cascade. We have investigated whether the observed strong neurotoxic potential of quercetin in primary cortical neurons may occur via specific and sensitive interactions within neuronal mitogen-activated protein kinase and Akt/protein kinase B (PKB) signaling cascades, both implicated in neuronal apoptosis. Quercetin induced potent inhibition of both Akt/PKB and ERK phosphorylation, resulting in reduced phosphorylation of BAD and a strong activation of caspase-3. High quercetin concentrations (30 μm) led to sustained loss of Akt phosphorylation and subsequent Akt cleavage by caspase-3, whereas at lower concentrations (