Modulations of critical cell cycle regulatory events during chemoprevention of ultraviolet B-mediated responses by resveratrol in SKH-1 hairless mouse skin.
Multiple exposures to solar ultraviolet (UV) radiation cause critical damages that may lead to the development of several cutaneous disorders including skin cancer, the most frequently diagnosed malignancy in the USA. Therefore, efforts are needed to: (i) study the mechanism(s) of UV-mediated cutaneous damages, and (ii) design novel approaches for the management of skin cancer. 'Chemoprevention' via plant-based agents may be a useful approach for the management of neoplasia. Here, we evaluated the involvement of cell cycle regulatory molecules during resveratrol-mediated protection from multiple exposures of UVB (180 mJ/cm(2); on alternate days x 7 exposures) radiations in the SKH-1 hairless mouse skin. Resveratrol was topically applied on the skin of SKH-1 hairless mice at a dose of 10 micromol/mouse (in 0.2 ml acetone; 30 min prior to each UVB exposure). Studies were performed at 24 h following the last UVB exposure. Topical application of resveratrol resulted in significant decrease in UVB-induced bi-fold skin thickness, hyperplasia, and infiltration of leukocytes. The data from immunoblot and/or immunohistochemical analyses revealed that multiple exposure to UVB radiations causes significant upregulation in: (i) proliferating cell nuclear antigen (PCNA), a marker of cellular proliferation, and (ii) cyclin-dependent kinase (cdk)-2, -4 and -6, cyclin-D1, and cyclin-D2. Resveratrol treatment resulted in significant downregulation in UV-mediated increases in these critical cell cycle regulatory proteins. An interesting observation of this study was that resveratrol treatment resulted in a further stimulation of UVB-mediated increases in cyclin kinase inhibitor WAF1/p21 and tumor suppressor p53. Further, resveratrol was also found to cause significant decreases in UVB-mediated upregulation of: (i) the mitogen-activated protein kinase kinase, and (ii) the 42 kDa isotype of mitogen-activated protein kinase (MAPK). Thus, our data suggested that the antiproliferative effects of resveratrol might be mediated via modulation in the expression and function of cell cycle regulatory proteins cyclin-D1 and -D2, cdk-2, -4 and -6, and WAF1/p21. Our data further suggest that the modulation of cki-cyclin-cdk network by resveratrol may be associated with inhibition of the MAPK pathway. We suggest that resveratrol may be useful for the prevention of UVB-mediated cutaneous damages including skin cancer.
Reagan-Shaw
Shannon
S
Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA.
Afaq
Farrukh
F
Aziz
Moammir Hasan
MH
Ahmad
Nihal
N
D000287:Administration, Topical; D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000528:radiation effects; D016213:Cyclins / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D007150:Immunohistochemistry; D007962:Leukocytes / Q000187:drug effects; D051379:Mice; D008812:Mice, Hairless; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects; D015394:Molecular Structure; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011833:Radiation Injuries, Experimental / Q000473:pathology / Q000517:prevention & control*; D000077185:Resveratrol; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D013267:Stilbenes / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects; D014466:Ultraviolet Rays / Q000009:adverse effects*; D015854:Up-Regulation
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018809:Proliferating Cell Nuclear Antigen; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D018844:Cyclin-Dependent Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D000077185:Resveratrol