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Fyn Inhibition by prenylated pholyphenols Leads to Antioxidant Effect through LKB1 Activation

Fyn, a kinase activated by oxidative stress, may play an important role in diverse pathological processes. This study investigated the effect of Fyn inhibition on LKB1‐mediated AMPK activation and cellular antioxidant capacity, and the effects of prenylated polyphenols (Prenyl‐PP) on the events. Prenyl‐PPs had an antioxidant effect, as indicated by diminished production of H2O2 and increased cell viability more potently than non‐prenlyated polyphenols, such as tupichinol and resveratrol. Treatment of HepG2 cells with Prenyl‐PP diminished mitochondrial permeability transition and superoxide production elicited by severe oxidative stress. Prenyl‐PP treatment activated LKB1, leading to the activation of AMPK responsible for the protection of mitochondria. Our in vitro and in cell kinase assays supported the ability of Prenyl‐PP to inhibit Fyn phosphorylation. The inhibitory role of Fyn in LKB1‐dependent AMPK activation was strengthened by the results of Fyn overexpression or knockdown experiments. SU6656 (a Fyn inhibitor) treatment exerted a similar effect. Furthermore, Prenyl‐PP treatment antagonized Fyn phosphorylation increased by oxidative stress, which was accompanied by the restoration of LKB1 activity. Our results demonstrate that the inhibition of Fyn contributes to LKB1‐mediated AMPK activation, thereby enhancing antioxidant effect, and which was accomplished by prenyl‐PP treatment.