Naringenin targets ERK2 and suppresses UVB‐induced photoaging

• Published in: Journal of cellular and molecular medicine 2016-05, Vol.20 (5), p.909-919
• Main Authors: Jung, Sung Keun, Ha, Su Jeong, Jung, Chang Hwa, Kim, Yun Tai, Lee, Hoo‐Keun, Kim, Myoung Ok, Lee, Mee‐Hyun, Mottamal, Madhusoodanan, Bode, Ann M., Lee, Ki Won, Dong, Zigang
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Biotechnology; Butadienes - pharmacology; Cell Culture Techniques; Cell Line; Enzyme inhibitors; Erythema; Extracellular signal-regulated kinase; extracellular signal‐regulated kinase 2; Female; Flavanones - pharmacology; Flavonoids; Fos‐related antigen 1; Fra1 protein; Gene Expression Regulation; Genes, Reporter; Hairless; Humans; Immunoglobulins; Irradiation; Keratinocytes - cytology; Keratinocytes - drug effects; Keratinocytes - metabolism; Keratinocytes - radiation effects; Kinases; Luciferases - genetics; Luciferases - metabolism; Matrix metalloproteinase; Matrix Metalloproteinase 1 - genetics; Matrix Metalloproteinase 1 - metabolism; matrix metalloproteinase‐1; MEK inhibitors; Metalloproteinase; Mice; Mice, Hairless; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Moisture content; Motility; Naringenin; Nitriles - pharmacology; Original; Phosphorylation; Phosphorylation - drug effects; Phosphorylation - radiation effects; photoaging; Protein expression; Protein kinase; Proteins; Proto-Oncogene Proteins c-fos - antagonists & inhibitors; Proto-Oncogene Proteins c-fos - genetics; Proto-Oncogene Proteins c-fos - metabolism; Ribosomal Protein S6 Kinases, 90-kDa - antagonists & inhibitors; Ribosomal Protein S6 Kinases, 90-kDa - genetics; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; Skin; Skin Aging - drug effects; Skin Aging - genetics; Skin Aging - pathology; Studies; Sunscreening Agents - pharmacology; Transcription Factor AP-1 - antagonists & inhibitors; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - metabolism; Tumors; Ultraviolet radiation; Ultraviolet Rays - adverse effects; Water - metabolism; Water content; Water loss
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.12780

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/cm2) 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 FRA1 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 (ERK2) activity and subsequently attenuated UVB‐induced phosphorylation of p90RSK by competitively binding with ATP. Constitutively active MEK (CA‐MEK) increased FRA1 phosphorylation and expression and also induced MMP‐1 expression, whereas dominant‐negative ERK2 (DN‐ERK2) had opposite effects. U0126, a MEK inhibitor, also decreased FRA1 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 ERK2 activity and decreasing FRA1 stability, followed by down‐regulation of AP‐1 transactivation and MMP‐1 expression.