The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Pyrithione-zinc Prevents UVB-induced Epidermal Hyperplasia by Inducing HIF-$1{\alpha}$

  • Cho, Young-Suk (Department of Pharmacology, Chungbuk National University College of Medicine) ;
  • Lee, Kyung-Hoon (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine) ;
  • Park, Jong-Wan (Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine)
  • Received : 2010.03.16
  • Accepted : 2010.04.10
  • Published : 2010.04.30
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Abstract

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-induce 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.

Keywords

References

  1. Melnikova VO, Ananthaswamy HN. Cellular and molecular events leading to the development of skin cancer. Mutat Res. 2005;571:91-106. https://doi.org/10.1016/j.mrfmmm.2004.11.015
  2. Marrot L, Meunier JR. Skin DNA photodamage and its biological consequences. J Am Acad Dermatol. 2008;58:S139-S148. https://doi.org/10.1016/j.jaad.2007.12.007
  3. Ouhtit A, Muller HK, Davis DW, Ullrich SE, McConkey D, Ananthaswamy HN. Temporal events in skin injury and the early adaptive responses in ultraviolet-irradiated mouse skin. Am J Pathol. 2000;156:201-207. https://doi.org/10.1016/S0002-9440(10)64720-7
  4. Lee JK, Kim JH, Nam KT, Lee SH. Molecular events associated with apoptosis and proliferation induced by ultraviolet-B radiation in the skin of hairless mice. J Dermatol Sci. 2003;32:171-179. https://doi.org/10.1016/S0923-1811(03)00094-X
  5. El-Abaseri TB, Putta S, Hansen LA. Ultraviolet irradiation induces keratinocyte proliferation and epidermal hyperplasia through the activation of the epidermal growth factor receptor. Carcinogenesis. 2006;27:225-231. https://doi.org/10.1093/carcin/bgi220
  6. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 1995;270:1230-1237. https://doi.org/10.1074/jbc.270.3.1230
  7. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL. Cellular and developmental control of $O_2 $ homeostasis by hypoxia-inducible factor $1\alpha$. Genes Dev. 1998;12:149-162. https://doi.org/10.1101/gad.12.2.149
  8. Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE. HIF-$1\alpha$ induces cell cycle arrest by functionally counteracting Myc. EMBO J. 2004;23:1949-1956. https://doi.org/10.1038/sj.emboj.7600196
  9. Cho YS, Bae JM, Chun YS, Chung JH, Jeon YK, Kim IS, Kim MS, Park JW. HIF-$1\alpha$ controls keratinocyte proliferation by up-regulating p21(WAF1/Cip1). Biochim Biophys Acta. 2008; 1783:323-333. https://doi.org/10.1016/j.bbamcr.2007.11.017
  10. Cho YS, Kim CH, Park JW. Involvement of HIF-$1\alpha$ in UVBinduced epidermal hyperplasia. Mol Cells. 2009;28:537-543. https://doi.org/10.1007/s10059-009-0148-2
  11. Chun YS, Choi E, Kim GT, Lee MJ, Lee MJ, Lee SE, Kim MS, Park JW. Zinc induces the accumulation of hypoxia-inducible factor (HIF)-$1\alpha$, but inhibits the nuclear translocation of HIF-$1\beta$, causing HIF-1 inactivation. Biochem Biophys Res Commun. 2000;268:652-656. https://doi.org/10.1006/bbrc.2000.2180
  12. Lim JH, Park JW, Kim MS, Park SK, Johnson RS, Chun YS. Bafilomycin induces the p21-mediated growth inhibition of cancer cells under hypoxic conditions by expressing hypoxiainducible factor-$1\alpha$. Mol Pharmacol. 2006;70:1856-1865. https://doi.org/10.1124/mol.106.028076
  13. Cho H, Lee HY, Ahn DR, Kim SY, Kim S, Lee KB, Lee YM, Park H, Yang EG. Baicalein induces functional hypoxia-inducible factor-$1\alpha$ and angiogenesis. Mol Pharmacol. 2008;74:70-81. https://doi.org/10.1124/mol.107.040162
  14. Weinreb O, Amit T, Youdim MB. A novel approach of proteomics and transcriptomics to study the mechanism of action of the antioxidant-iron chelator green tea polyphenol (-)-epigallocatechin- 3-gallate. Free Radic Biol Med. 2007;43:546-556. https://doi.org/10.1016/j.freeradbiomed.2007.05.011
  15. Park SE, Park JW, Cho YS, Ryu JH, Paick JS, Chun YS. HIF-$1\alpha$ promotes survival of prostate cells at a high zinc environment. Prostate. 2007;67:1514-1523. https://doi.org/10.1002/pros.20641
  16. Huang LE, Gu J, Schau M, Bunn HF. Regulation of hypoxiainducible factor $1\alpha$ is mediated by an $O_2$-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A. 1998;95:7987-7992. https://doi.org/10.1073/pnas.95.14.7987
  17. Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol. 2004;5:343-354. https://doi.org/10.1038/nrm1366
  18. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT. Regulation of hypoxiainducible factor $1\alpha$ expression and function by the mammalian target of rapamycin. Mol Cell Biol. 2002;22:7004-7014. https://doi.org/10.1128/MCB.22.20.7004-7014.2002
  19. Lang KJ, Kappel A, Goodall GJ. Hypoxia-inducible factor- $1\alpha$ mRNA contains an internal ribosome entry site that allows efficient translation during normoxia and hypoxia. Mol Biol Cell. 2002;13:1792-1801. https://doi.org/10.1091/mbc.02-02-0017
  20. Arsham AM, Plas DR, Thompson CB, Simon MC. Phosphatidylinositol 3-kinase/Akt signaling is neither required for hypoxic stabilization of HIF-$1\alpha$ nor sufficient for HIF-1-dependent target gene transcription. J Biol Chem. 2002;277:15162-15170. https://doi.org/10.1074/jbc.M111162200
  21. Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-$1\alpha$-degradative pathway. J Biol Chem. 2002;277:29936-29944. https://doi.org/10.1074/jbc.M204733200
  22. Luo W, Zhong J, Chang R, Hu H, Pandey A, Semenza GL. Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-$1\alpha$ but Not HIF-$2\alpha$. J Biol Chem. 2010;285:3651-3663. https://doi.org/10.1074/jbc.M109.068577
  23. Pierard-Franchimont C, Goffin V, Decroix J, Pierard GE. A multicenter randomized trial of ketoconazole 2% and zinc pyrithione 1% shampoos in severe dandruff and seborrheic dermatitis. Skin Pharmacol Appl Skin Physiol. 2002;15:434-441. https://doi.org/10.1159/000066452
  24. Bailey P, Arrowsmith C, Darling K, Dexter J, Eklund J, Lane A, Little C, Murray B, Scott A, Williams A, Wilson D. A doubleblind randomized vehicle-controlled clinical trial investigating the effect of ZnPTO dose on the scalp vs. antidandruff efficacy and antimycotic activity. Int J Cosmet Sci. 2003;25: 183-188. https://doi.org/10.1046/j.1467-2494.2003.00183.x
  25. Guthery E, Seal LA, Anderson EL. Zinc pyrithione in alcoholbased products for skin antisepsis: persistence of antimicrobial effects. Am J Infect Control. 2005;33:15-22. https://doi.org/10.1016/j.ajic.2004.07.012

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