Src kinase is a direct target of apigenin against UVB-induced skin inflammation

Abstract

Apigenin, a flavonoid abundant in various vegetables and fruits, including parsley and onions, has been reported to possess anticarcinogenic effects. However, the direct molecular target of apigenin and its chemopreventive effect on ultraviolet (UV)-induced skin inflammation are not understood fully. Herein, we examined the anti-inflammatory effect of apigenin and its associated mechanisms in JB6 P+ cell line and SKH-1 hairless mouse model. Apigenin inhibited UVB-induced cyclooxygenase-2 (COX-2) expression, which is a well-known key mediator of inflammation and cancer, and restored the upstream stimulatory factor level in JB6 P+ cells. Immunoblot and kinase assay data demonstrate that Src activity was attenuated by apigenin, and this led to subsequent inhibition of UVB-induced phosphorylation of epidermal growth factor receptor, mitogen-activated protein kinases and Akt signaling. Inhibitory effects of apigenin on UVB-induced signaling were also confirmed in HaCaT human keratinocytes. In addition, in vitro pull-down assays revealed that apigenin binds Src in an adenosine triphosphate-competitive manner. Results using in vivo skin model indicate apigenin significantly inhibits UVB-induced ear edema development, COX-2 expression and Src kinase activity in SKH-1 hairless mice. Collectively, these findings suggest that apigenin exerts potent chemopreventive activity against UVB-induced skin inflammation primarily by targeting Src.

GRID and docking analyses reveal a molecular basis for flavonoid inhibition of Src family kinase activity

“…Therefore, apigenin may be less potent than quercetin due to lower affinity caused by omission of the C ring C-10 hydroxyl from the structure of the flavone. Apigenin may be more selective for Src than for Lyn, Fyn and Hck, as previous studies demonstrate; in in vitro pull-down assays the flavone binds Src in an adenosine triphosphate-competitive manner[48].Within the ATP binding pocket of Lyn (Figure 5E. and 5F.…”

Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways

“…Previous studies have also reported multiple JAK2 inhibitors that maintained or increased the phosphorylation levels of JAK2 (44,45). In addition, inhibitors for other kinases have been shown to not affect the phosphorylation levels of the target kinase, whereas the activity was inhibited by the compounds (51)(52)(53). A possible explanation might be that a negative feedback pathway occurs after inhibition of JAK2 such that a hyperactivated upstream kinase could increase the phosphorylation level.…”

Skin anti‐inflammatory activity of rose petal extract (Rosa gallica) through reduction of MAPK signaling pathway

“…We adopted the excessive sUV exposure‐related skin inflammation model, as over‐exposure of skin to UV is a physiological stimulator of skin inflammation (Lopes & Mcmahon, 2016). The JB6 P+ cell line is an optimized model for studying skin inflammation owing to its sensitivity to inflammatory enhancers such as UV, EGFR, and 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) (Byum et al., 2013; Chen et al., 2001). We found that COX‐2 expression induced by sUV irradiation is dose‐dependently attenuated by RPE treatment.…”