Pyrithione-zinc Prevents UVB-induced Epidermal Hyperplasia by Inducing HIF-1 alpha

Epidermal keratinocytes overgrow in response to ultraviolet-B (UVB), which may be associated with skin photoaging and cancer development. Recently, we found that HIF-1 alpha controls the keratinocyte cell cycle and thereby contributes to epidermal homeostasis. A further study demonstrated that HIF-1 alpha is down-regulated by UVB and that this process is involved in UVB-induced skin hyperplasia. Therefore, we hypothesized that the forced expression of HIF-1 alpha in keratinocytes would prevent UVB-induced keratinocyte overgrowth. Among several agents known to induce HIF-1 alpha, pyrithione-zinc (Py-Zn) overcame the UVB suppression of HIF-1 alpha in cultured keratinocytes. Mechanistically, Py-Zn blocked the degradation of HIF-1 alpha protein in keratinocytes, while it did not affect the synthesis of HIF-1 alpha. Moreover, the p21 cell cycle inhibitor was down-regulated after UVB exposure, but was robustly induced by Py-Zn. In mice repeatedly irradiated with UVB, the epidermis became hyperplastic and HIF-1 alpha disappeared from nuclei of epidermal keratinocytes. However, a cream containing Py-Zn effectively prevented the skin thickening and up-regulated HIF-1 alpha to the normal level. These results suggest that Py-Zn is a potential agent to prevent UVB-induced photoaging and skin cancer development. This work also provides insight into a molecular target for treatment of UVB-induced skin diseases.Luo WB, 2010, J BIOL CHEM, V285, P3651, DOI 10.1074/jbc.M109.068577Cho YS, 2009, MOL CELLS, V28, P537, DOI 10.1007/s10059-009-0148-2Cho H, 2008, MOL PHARMACOL, V74, P70, DOI 10.1124/mol.107.040162Marrot L, 2008, J AM ACAD DERMATOL, V58, pS139, DOI 10.1016/j.jaad.2007.12.007Cho YS, 2008, BBA-MOL CELL RES, V1783, P323, DOI 10.1016/j.bbamcr.2007.11.017Park SE, 2007, PROSTATE, V67, P1514, DOI 10.1002/pros.20641Weinreb O, 2007, FREE RADICAL BIO MED, V43, P546, DOI 10.1016/j.freeradbiomed.2007.05.011Lim JH, 2006, MOL PHARMACOL, V70, P1856, DOI 10.1124/mol.106.028076El-Abaseri TB, 2006, CARCINOGENESIS, V27, P225, DOI 10.1093/carcin/bgi220Melnikova VO, 2005, MUTAT RES-FUND MOL M, V571, P91, DOI 10.1016/j.mrfmmm.2004.11.015Guthery E, 2005, AM J INFECT CONTROL, V33, P15, DOI 10.1016/j.ajic.2004.07.012Koshiji M, 2004, EMBO J, V23, P1949, DOI 10.1038/sj.emboj.7600196Schofield CJ, 2004, NAT REV MOL CELL BIO, V5, P343, DOI 10.1038/nrm1366Lee JK, 2003, J DERMATOL SCI, V32, P171, DOI 10.1016/S0923-1811(03)00094-XBAILEY P, 2003, INT J COSMETIC SCI, V25, P183Pierard-Franchimont C, 2002, SKIN PHARMACOL APPL, V15, P434, DOI 10.1159/000066452Hudson CC, 2002, MOL CELL BIOL, V22, P7004, DOI 10.1128/MCB.22.20.7004-7014.2002Isaacs JS, 2002, J BIOL CHEM, V277, P29936, DOI 10.1074/jbc.M204733200Lang KJD, 2002, MOL BIOL CELL, V13, P1792, DOI 10.1091/mbc.02-02-0017Arsham AM, 2002, J BIOL CHEM, V277, P15162, DOI 10.1074/jbc.M111162200Chun YS, 2000, BIOCHEM BIOPH RES CO, V268, P652Ouhtit A, 2000, AM J PATHOL, V156, P201Huang LE, 1998, P NATL ACAD SCI USA, V95, P7987Iyer NV, 1998, GENE DEV, V12, P149WANG GL, 1995, J BIOL CHEM, V270, P1230