Open AccessNaringenin targets ERK 2 and suppresses UVB ‐induced photoaging
Author(s) -
Jung Sung Keun,
Ha Su Jeong,
Jung Chang Hwa,
Kim Yun Tai,
Lee HooKeun,
Kim Myoung Ok,
Lee MeeHyun,
Mottamal Madhusoodanan,
Bode Ann M.,
Lee Ki Won,
Dong Zigang
Publication year - 2016
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12780
Subject(s) - naringenin , photoaging , mapk/erk pathway , chemistry , biology , biochemistry , phosphorylation , antioxidant , flavonoid , genetics
A number of natural phytochemicals have anti‐photoaging properties that appear to be mediated through the inhibition of matrix metalloproteinase‐1 ( MMP ‐1) expression, but their direct target molecule(s) and mechanism(s) remain unclear. We investigated the effect of naringenin, a major flavonoid found in citrus, on UVB ‐induced MMP ‐1 expression and identified its direct target. The HaCaT human skin keratinocyte cell line and 3‐dimensional (3‐D) human skin equivalent cultures were treated or not treated with naringenin for 1 hr before exposure to UVB . The mechanism and target(s) of naringenin were analysed by kinase assay and multiplex molecular assays. Dorsal skins of hairless mice were exposed to UVB 3 times per week, with a dose of irradiation that was increased weekly by 1 minimal erythema dose ( MED ; 45 mJ/cm 2 ) to 4 MED over 15 weeks. Wrinkle formation, water loss and water content were then assessed. Naringenin suppressed UVB ‐induced MMP ‐1 expression and AP ‐1 activity, and strongly suppressed UVB ‐induced phosphorylation of Fos‐related antigen ( FRA )‐1 at Ser265. Importantly, UVB irradiation‐induced FRA 1 protein stability was reduced by treatment with naringenin, as well as with a mitogen‐activated protein kinase ( MEK ) inhibitor. Naringenin significantly suppressed UVB ‐induced extracellular signal‐regulated kinase 2 ( ERK 2) activity and subsequently attenuated UVB ‐induced phosphorylation of p90 RSK by competitively binding with ATP . Constitutively active MEK ( CA ‐ MEK ) increased FRA 1 phosphorylation and expression and also induced MMP ‐1 expression, whereas dominant‐negative ERK 2 ( DN ‐ ERK 2) had opposite effects. U0126, a MEK inhibitor, also decreased FRA 1 phosphorylation and expression as well as MMP ‐1 expression. The photoaging data obtained from mice clearly demonstrated that naringenin significantly inhibited UVB ‐induced wrinkle formation, trans‐epidermal water loss and MMP ‐13 expression. Naringenin exerts potent anti‐photoaging effects by suppressing ERK 2 activity and decreasing FRA 1 stability, followed by down‐regulation of AP ‐1 transactivation and MMP ‐1 expression.