Vitamin E analog modulates UVB-induced signaling pathway activation and enhances cell survival.
We have recently shown that exposure of human keratinocytes to physiologic doses of ultraviolet B (UVB) activates epidermal growth factor receptor (EGFR)/extracellular-regulated kinases 1 and 2 (ERK1/2) and p38 signaling pathways via reactive oxygen species, an effect that can be modulated by antioxidants. Trolox, a water-soluble vitamin E analog, is among the antioxidants that are currently being investigated for their preventive and protective potential against harmful effects of UV radiation to the skin. We found that Trolox inhibits both basal and UVB-induced intracellular H(2)O(2) generation in primary keratinocytes in a concentration-dependent manner. Trolox did not significantly affect UVB-induced phosphorylation of EGFR. Stronger inhibition was observed for ERK1/2 activation at lower, and for p38 activation at higher, concentrations of Trolox added to cells before exposure to UVB. Similarly different effects were found with regard to length of pretreatment with Trolox before UVB exposure-increasing inhibition for ERK1/2 activation at shorter, and for p38 activation at longer, pretreatment intervals. UVB-induced c-jun-N-terminal kinase activation was potently suppressed by Trolox. Also, increasing the pretreatment time of Trolox decreased the rate of cell death following UVB. In conclusion, UVB-induced signaling pathway activation is differentially modulated by Trolox. Further investigation into the time-dependent biologic activation of Trolox and its metabolic products, and modulation of signal transduction with cell outcome should facilitate development of rational strategies for pharmacologic applications.
Peus
D
D
Departments of Dermatology and Biochemistry and Molecular Biology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
Meves
A
A
Pott
M
M
Beyerle
A
A
Pittelkow
M R
MR
D000975:Antioxidants / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002839:Chromans / Q000008:administration & dosage / Q000494:pharmacology*; D005434:Flow Cytometry; D005609:Free Radicals; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007231:Infant, Newborn; D048031:JNK Mitogen-Activated Protein Kinases; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D048670:MAP Kinase Kinase 4; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D014466:Ultraviolet Rays / Q000009:adverse effects; D014810:Vitamin E / Q000031:analogs & derivatives
D000975:Antioxidants; D002839:Chromans; D005609:Free Radicals; D017382:Reactive Oxygen Species; D014810:Vitamin E; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid