An Arachidonic Acid Metabolizing Enzyme, 8S-Lipoxygenase, in Mouse Skin Carcinogenesis

  • Kim Eun-Jung (Life Sciences Institute, University of Michigan)
  • Published : 2006.08.01


The involvement of arachidonic acid (AA) metabolizing enzyme, lipoxygenase (LOX), in the development of particular tumors in humans has gradually been acknowledged and LOX has emerged as a novel target to prevent or treat human cancers. In the mouse skin carcinogenesis model, which provides an excellent model to study multistage nature of human cancer development, many studies have shown that some of the LOXs are constitutively upregulated in their expression. Moreover, application of LOX inhibitors effectively reduced tumor burdens, which implicates the involvement of LOX in mouse skin tumor development as well. 8S-LOX is a recently cloned LOX, which is specifically expressed in mouse skin after 12-O-tetradecanoyl-phorbol-13-acetate (TPA) treatment but not in normal skin. Unlike other members of the LOX 'family' expressed in mouse skin, this TPA-induced expression of 8S-LOX is prominent only in the skin of the TPA tumor promotion-sensitive strains of mice (SENCAR, CD-1, and NMRI) but not in the promotion-resistant C57BL/6J mice. This is a very unique phenomenon among strains of mice. Constitutive upregulation of 8S-LOX was also found in early stage papillomas and the expression was gradually reduced as the tumors became malignant. Based on these observations, it has been thought that 8S-LOX is involved in TPA-induced tumor promotion as well as in tumor conversion from papillomas to carcinomas. In accordance with this hypothesis, several studies have suggested possible roles of 8S-hydroxyeicosatetraenoic acid (HETE), an AA metabolite of 8S-LOX, in mouse skin tumor development. A clastogenic activity of 8S-HETE was demonstrated in primary keratinocytes and a close correlation between the levels of etheno-DNA adducts and 8S-HETE during skin carcinogenesis was also reported. On the other hand, it has been reported that 8S-LOX protein expression is restricted to a differentiated keratinocyte compartment Moreover, reported findings on the ability of 8S-HETE to cause keratinocyte differentiation appear to be contrary to the procarcinogenic features of the 8S-LOX expression, presenting a question as to the role of 8S-LOX during mouse skin carcinogenesis. In this review, molecular and biological features of 8S-LOX as well as current views on the functional role of 8S-LOX/8S-HETE during mouse skin carcinogenesis are presented.


  1. Iversen L, Kragballe K. Arachidonic acid metabolism in skin health and disease. Prostaglandins Other Lipid Mediat 63:25-42, 2000
  2. Chapkin RS, Ziboh VA, Marcelo CL, Voorhees JJ. Metabolism of essential fatty acids by human epidermal enzyme preparations: evidence of chain elongation. J Lipid Res 27:945-954, 1986
  3. Ruzicka T, Printz MP. Arachidonic acid metabolism in skin: a review. Rev Physiol Biochem Pharmacol 100:121-160, 1984
  4. Marks F, Muller-Decker K, Furstenberger G. A causal relationship between unscheduled eicosanoid signaling and tumor development cancer chemoprevention by inhibitors of arachidonic acid metabolism. Toxicol 153: 11-26, 2000
  5. Fischer SM. Prostaglandins and cancer. Front Biosci 2:d482-500, 1997
  6. Steinbach G, Lynch PM, Phillips RK, H WM, Hawk E, Gordon GB, Wakabayashi N, Saunders B, Shen Y, Fujumura T, Su LK, Levin B. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342:1946-1952, 2000
  7. Steele VE, Holmes CA, Hawk ET, Kopelovich L, Lubet RA, Crowell JA, Sigman CC, Kelloff GJ. Lipoxygenase inhibitors as potential cancer chemopreventives. Cancer Epidemiol Biomarkers Prev 8:467-483, 1999
  8. Shureiqi I, Lippman SM. Lipoxygenase modulation to reverse carcinogenesis. Cancer Res 61:6307-6312, 2001
  9. Fischer SM, Klein RD. Lipoxygenases as targets for cancer prevention. Humana Press Inc., Totowa, 2003
  10. Herschman HR. Regulation of prostaglandin synthase-1 and prostaglandin synthase-2. Cancer Metast Rev 13:241-256, 1994
  11. Goppelt-Struebe M. Regulation of prostaglandin endoperoxide synthase (cyclooxygenase) isozyme expression. Prostaglandin Leukot and Essent Fatty Acids 52:213-222, 1995
  12. Gschwendt M, Furstenberger G, Kittstein W, Besemfelder E, Hull WE, Hagedorn H, Opferkuch HJ, Marks F. Generation of the arachidonic acid metabolite 8-HETE by extracts of mouse skin treated with phorbol ester in vivo; identification by H-n.m.r. and GC-MS spectroscopy. Carcinogenesis 7:449-455, 1986
  13. Furstenberger G, Hagedorn H, Jacobi T, Besemfelder E, Stephan M, Lehmann WD, Marks F. Characterization of an 8-Lipoxygenase activity induced by the phorbol ester tumor promoter 12-O-Tetradecanoylphorbol-13-acetate in mouse skin in vivo. J Biol Chem 266:15738-15745, 1991
  14. Jisaka M, Kim RB, Boeglin WE, Nanney LB, Brash AR. Molecular cloning and functional expression of a phorbol esterinducible 8S-lipoxygenase from mouse skin. J Biol Chem 272:24410-24416, 1997
  15. Burger F, Krieg P, Kinzig A, Schurich B, Marks F, Furstenberger G. Constitutive expression of 8-lipoxygenase in papillomas and clastogenic effects of lipoxygenase-derived arachidonic acid metabolites in keratinocytes. Mol Carcinog 24:108-117, 1999<108::AID-MC5>3.0.CO;2-R
  16. Eckert RL. Structure, function, and differentiation of the keratinocyte. Physiol Rev 69:1316-1346, 1989
  17. Fuchs E, Green H. Changes in keratin gene expression during terminal differentiation of the keratinocyte. Cell 19:1033-1042, 1980
  18. Woodcock-Mitchell J, Eichner R, Nelson WG, Sun TT. Immunolocalization of keratin polypeptides in human epidermis using monoclonal antibodies. J Cell Biol 95:580-588, 1982
  19. Roop DR, Hawley-Nelson P, Cheng CK, Yuspa SH. Keratin gene expression in mouse epidermis and cultured epidermal cells. Proc Natl Acad Sci USA 80:716-720, 1983
  20. Odland GF. Structure of the Skin. In:Goldsmith LA, ed. Biochemistry and Physiology of the Skin, Vol. 1, pp.3-63, Oxford University Press, New York, 1983
  21. Banks-Schlegel S, Green H. Involucrin synthesis and tissue assembly by keratinocytes in natural and cultured human epithelia. J Cell Biol 90:732-737, 1981
  22. Mehrel T, Hohl D, Rothnagel JA, Longley MA, Bundman D, Cheng C, Lichti U, Bisher ME, Steven AC, Steinert PM, Yuspa SH, Roop DR Identification of a major keratinocyte cell envelope protein, loricrin. Cell 61:1103-1112, 1990
  23. Rothnagel JA, Mehrel T, Idler WW, Roop DR, Steinert PM. The gene for mouse epidermal filaggrin precursor. Its partial characterization, expression, and sequence of a repeating filaggrin unit. J Biol Chem 262:15643-15648, 1987
  24. Buxman MM, Wuepper KD. Epidermal transglutaminase. J Histochem Cytochem 26:340-348, 1978
  25. Scott IR, Harding CR, Barrett JG. Histidine-rich protein of the keratohyalin granules. Source of the free amino acids, urocanic acid and pyrrolidone carboxylic acid in the stratum corneum. Biochim Biophys Acta 719:110-117, 1982
  26. Siaga TJ, Fischer SM, Nelson K, Gleason GL. Studies on the mechanism of skin tumor promotion: Evidence for several stages in promotion. Proc Natl Acad Sci USA 77:3659-3663, 1980
  27. Siaga TJ, Klein-Szanto AJP, Fischer SM, Weeks CE, Nelson K, Major S. Studies on the mechanism of action of anti-tumor promoting agents: Their specificity in two-stage promotion. Proc Natl Acad Sci USA 77:2251-2254, 1980
  28. DiGiovanni J. Multistage carcinogenesis in mouse skin. Pharmacol Ther 54:63-128, 1992
  29. Kulesz-Martin MF. Biological aspects of multistage carcinogenesis as studied in experimental animals and in cell culture models. pp.7-30, Pergamon, New York, Oxford, Tokyo, 1997
  30. Mukhtar H, Mercurio MG, Agarwal R. Murine skin carcinogenesis: relevance to humans. In: Mukhtar H, ed. Skin Cancer: Mechanisms and Human Relevance, pp.3-8, CRC Press Inc., Boca Raton, 1995
  31. Farber E. Cellular biochemistry of the stepwise development of cancer with chemicals. Cancer Res 44:5463-5474, 1984
  32. Pitot HC, Dragan YP. Facts and theories concerning the mechanisms of carcinogenesis. FASEB J 5:2280-2286, 1991
  33. Quintanilla M, Brown K, Ramsden M, Balmain A. Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature 322:78-80, 1986
  34. Balmain A, Brown L. Oncogenic activation in chemical carcinogenesis. Adv Cancer Res 51:147-183, 1988
  35. Brown K, Buchmann A, Balmain A. Carcinogen-induced mutations in the mouse c-Ha-ras gene provide evidence of multiple pathways for tumor progression. Proc Natl Acad Sci USA 87:538-542, 1990
  36. Bowden GT, Finch J, Domann F, Krieg P. Molecular mechanisms involved in skin tumor initiation, promotion, and progression. In: Mukhtar H, ed. Skin Cancer: Mechanisms and Human Relevance, pp.99-111, CRC Press Inc., Boca Raton, 1995
  37. Slaga TJ. Mechanisms involved in two-stage carcinogenesis in mouse skin. pp.1-16, CRC Press Inc., Boca Raton, 1984
  38. Winberg LD, Budunova IV, Warren BS, Lyer RP, Slaga TJ. Mechanisms of skin tumor promotion and progression. In Mukhtar H, ed. Skin Cancer: Mechanisms and Human Relevance, pp.113-120, CRC Press Inc., Boca Raton, 1995
  39. Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem 257:7847-7851, 1982
  40. Niedel JE, Kuhn LU, Vandenbark GR. Phorbol diester receptor copurifies with protein kinase C. Proc Natl Acad Sci USA 80:36-40, 1983
  41. Kuroki T, lkuta T, Kasahara K, Kohno Y, Koizumi H, Chida K. Possible roles of protein kinase C isoforms in growh, differentiation, and carcinogenesis of keratinocytes. pp.121-127, CRC Press, Boca Raton, 1995
  42. Marks F, Furstenberger G. Cancer chemoprevention through interruption of multistage carcinogenesis: the lessons learnt by comparing mouse skin carcinogenesis and human large bowel cancer. Eur J Cancer 36:314-329, 2000
  43. Matrisian LM, Bowden GT, Krieg P, Furstenberger G, Briand JP, Leroy P, Breathnach R. The mRNA coding for the secreted protease transin is expressed more abundantly in malignant than in benign tumors. Proc Natl Acad Sci USA 83:9413-9417, 1986
  44. Ostrowski LE, Finch J, Krieg P, Matrisian L, Patskan G, O'Connell JF, Phillips J, Slaga TJ, Breathnach R, Bowden GT. Expression pattern of a gene for a secreted metalloproteinase during late stages of tumor progression. Mol Carcinog 1:13-19, 1988
  45. Boyington JC, Gaffney BJ, Amzel LM. The three-dimensional structure of an arachidonic acid 15-lipoxygenase. Science 260:1482-1486, 1993
  46. Prigge ST, Boyington JC, Faig M, Doctor KS, Gaffney BJ, Amzel LM. Structure and mechanism of lipoxygenases. Biochimie 79:629-636, 1997
  47. Kuhn H, Schewe T, Rapoport SM. The stereochemistry of the reactions of lipoxygenases and their metabolites: Proposed nomenclature of lipoxygenases and related enzymes. Adv Enzymol Relat Areas Mol Biol 58:273-311, 1986
  48. Brash AR, Boeglin WE, Chang MS, Shieh BH. Purification and molecular cloning of an 8R-lipoxygenase from the coral Plexaura homomalla reveal the related primary structuresof R-and S-lipoxygenases. J Biol Chem 271:20949-20957, 1996
  49. Krieg P, Kinzig A, Heidt M, Marks F, Furstenberger G. cDNA cloning of a 8-lipoxygenase and a novel epidermis-type lipoxygenase from phorbol ester-treated mouse skin. Biochim Biophys Acta 1391:7-12, 1998
  50. Boeglin WE, Kim RB, Brash AR. A 12R-lipoxygenase in human skin: mechanistic evidence, molecular cloning, and expression. Proc Natl Acad Sci USA 95:6744-6749, 1998
  51. Gerwick WH. Structure and biosynthesis of marine algal oxylipins. Biochim Biophys Acta 1211:243-255, 1994
  52. De Petrocellis L, Di Marzo V. Aquatic invertebrates open up new perspectives in eicosanoid research: biosynthesis and bioactivity. Prostaglandins Leukot Essent Fatty Acids 51:215-229, 1994
  53. Funk CD. The molecular biology of mammalian lipoxygenases and the quest for eicosanoid functions using lipoxygensedeficient mice. Biochim Biophys Acta 1304:65-84, 1996
  54. Yamamoto S, Suzuki H, Ueda N. Arachidonate 12-lipoxygenases. Prog Lipid Res 36:23-41, 1997
  55. Grechkin A. Recent developments in biochemistry of the plant lipoxygenase pathway. Prog Lipid Res 37:317-352, 1998
  56. Brash AR. Lipoxygenases: occurrence, functions, catalysis, and acquisition of substrate. J Biol Chem 274:23679-23682, 1999
  57. Watanabe K, Ishikawa C, Ohtsuka I, Kamata M, Tomita M, Yazawa K, Muramatsu H. Lipid and fatty acid compositions of a novel docosahexaenoic acid-producing marine bacterium. Lipids 32:975-978, 1997
  58. Chen XS, Naumann TA, Kurre U, Jenkins NA, Copeland NG, Funk CD. cDNA cloning, expression, mutagenesis, intracellular localization, and gene chromosomal assignment of mouse 5-lipoxygenase. J Biol Chem 270: 17993-17999, 1995
  59. Krieg P, Kinzig A, Ress-Loschke M, Vogel S, Vanlandingham B, Stephan M, Lehmann WD, Marks F, Furstenberger G. 12-Lipoxygenase isoenzymes in mouse skin tumor development. Mol Carcinog 14: 118-129, 1995
  60. Kinzig A, Furstenberger G, Burger F, Vogel S, Muller-Decker K, Mincheva A, Lichter P, Marks F, Krieg P. Murine epidermal lipoxygenase (Aloxe) encodes a 12-lipoxygenase isoform, FEBS Lett 402:162-166, 1997
  61. Fischer SM, Mills GD, Slaga TJ. Inhibition of mouse skin tumor promotion by several inhibitors of arachidonic acid metabolism. Carcinogenesis 3:1243-1245, 1982
  62. Nakadate T, Yamamoto S, Iseki H, Sonoda S, Takemura S, Ura A, Hosoda Y, Kato R. Inhibiticm of 12-O-tetradecanoyl-phorbol-13-acetate-induced tumor promotion by nordihydroguaiaretic acid, a lipoxygenase inhibitor, and p-bromophenacyl bromide, a phospholipase A2 inhibitor. Gann 73:841-843, 1982
  63. Fischer SM, Mills GD, Slaga TJ. Modulation of skin tumor promotion by inhibitors of arachidonic acid metabolism. Adv Prostaglandin Thromboxane Leukot Res 12:309-312, 1983
  64. Kato R, Nakadate T, Yamamoto S, Sugimura T. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion and ornithine decarboxylase activity by quercetin: possible involvement of lipoxygenase inhibition. Carcinogenesis 4:1301-1305, 1983
  65. Fischer SM, Furstenberger G, Marks F, Slaga TJ. Events associated with mouse skin tumor promotion with respect to arachidcmic acid metabolism: A comparision between SENCAR and NMRI mice. Cancer Res 47:3174-3179, 1987
  66. Samuelsson B, Funk CD. Enzymes involved in the biosynthesis of leukotriene B4. J Biol Chem 264:19469-19472, 1989
  67. Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN. Leucotriens and lipoxins; structure, biosynthesis, and biological effects. Science 237: 1171-1176, 1987
  68. Furstenberger G, Csuk-Glanzer BI, Marks F, Keppler D. Phorbol ester-induced leukotriene biosynthesis and tumor promotion in mouse epidermis. Carcinogenesis 15:2823-2827, 1994
  69. Yamamoto S, Aizu E, Jiang H, Nakadate T, Kiyoto I, Wang JC, Kato R. The potent anti-tumor-promoting agent isoliquiritigenin. Carcinogenesis 12:317-323, 1991
  70. Jiang H, Yamamoto S, Kato R. Inhibition of two-stage skin carcinogenesis as well as complete skin carcinogenesis by oral administration of TMK688, a potent lipoxygenase inhibitor. Carcinogenesis 15:807-812, 1994
  71. Fischer SM, Baldwin JK, Jasheway DW, Patrick KE, Cameron GS. Phorbol ester induction of 8-lipoxygenase in inbred SENCAR (SSIN) but not C57BL/6J mice correlated with hyperplasia, edema, and oxidant generation but not ornithine decarboxylase induction. Cancer Res 48:658-664, 1988
  72. Siebert M, Krieg P, Lehmann WD, Marks F, Furstenberger G. Enzymic characterizaticm of epidermis-derived 12-lipoxygenase isoenzymes. Biochem J 355:97-104, 2001
  73. Johnson EN, Nanney LB, Virmani J, Lawson JA, Funk CD. Basal transepidermal water loss is increased in platelet -type 12-1ipoxygenase deficient mice. J Invest Dermatol 112:861-865, 1999
  74. Chang WC, Liu YW, Ning CC, Suzuki H, Yoshimoto T, Yamamoto S. Induction of arachidonate 12-lipoxygenase mRNA by epidermal growth factor in A431 cells. J Biol Chem 268:18734-18739, 1993
  75. Virmani J, Johnson EN, Klein-Szanto AJ, Funk CD. Role of 'platelet-type' 12-lipoxygenase in skin carcinogenesis. Cancer Lett 162:161-165, 2001
  76. Chan C, Duhamel L, Ford-Hutchison A. Leukotriene B4 and 12-hydroxyeicosatetraenoic acid stimulate epidermal proliferation in vivo in the guinea pig. J Invest Dermatol 85:333-334, 1989
  77. Dowd PM, Kobza Black A, Woollard PM, Camp RD, Greaves MW. Cutaneous responses to 12-hydroxy-5,8,10,14 -eicosate- traenoic acid (12-HETE). J Invest Dermatol 84:537-541, 1985
  78. Tang DG, Renaud C, Stojakovic S, Diglio CA, Porter A, Honn KV. 12(S)-HETE is a mitogenic factor for microvascular endothelial cells: its potential role in angiogenesis. Biochem Biophys Res Commu 211:462-468, 1995
  79. Tang DG, Honn KV. 12-Lipoxygenase, 12(S)-HETE, and cancer matastasis. Ann NY Acad Sci 744: 199-215, 1994
  80. Fischer SM, Hagerman RA, Li-Stiles E, La HH, Maldve RE, Belury MA, Locniskar MF. Arachidonate has protumor-promoting action that is inhibited by linoleate in mouse skin carcinogenesis. J Nutr 126:1099S-1104S, 1996
  81. Funk CD, Keeney DS, Oliw EH, Boeglin WE, Brash AR. Functional expression and cellular localization of a mouse epidermal lipoxygenase. J Biol Chem 271:23338-23344, 1996
  82. Kinzig A, Heidt M, Furstenberger G, Marks F, Krieg P. cDNA cloning, genomic structure, and chromosomal localization of a novel murine epidermis-type lipoxygenase. Genomics 58:158-164, 1999
  83. Muller K, Siebert M, Heidt M, Marks F, Krieg P, Furstenberger G. Modulation of epidermal tumor development caused by targeted overexpression of epidermis-type 12S-lipoxygenase. Cancer Res 62:4610-4616, 2002
  84. Kuhn H, Borngraber S. Mammalian 15-lipoxygenases: Enzymatic properties and biological implications. pp.5-28, Plenum Press, New York, 1999
  85. Fischer SM, Cameron GS, Baldwin JK, Jasheway DW, Patrick KE. Reactive oxygen in the tumor promotion stage of skin carcinogenesis. Lipids 23:592-597, 1988
  86. Nakadate T, Yamamoto S, Aizu E, Kato R. Effects of flavonoids and antioxidants on 12-O-tetradecanoyl-phorbol-13-acetatecaused epidermal ornithine decarboxylase induction and tumor promotion in relation to lipoxygenase inhibition by these compounds. Gann 75:214-222, 1984
  87. Katiyar SK, Agarwal R, Mukhtar H. Inhibition of tumor promotion in SENCAR mouse skin by ethanol extract of Zingiber officinale rhizome. Cancer Res 56: 1023-1030, 1996
  88. Singh RP, Agarwal R. Flavonoid antioxidant silymarin and skin cancer. Antioxid Redox Signal 4:655-663, 2002
  89. Hughes MA, Brash AR. Investigation of the mechanism of biosynthesis of 8-hydroxyeicosatetraenoic acid in mouse skin. Biochim Biophys Acta 1081:347-354, 1991
  90. Furstenberger G, Marks F, Krieg P. Arachidonate 8(S)lipoxygcnase, Prostaglandins Other lipid Mediat 68-69:235-243, 2002
  91. Jisaka M, Kim RB, Boeglin WE, Brash AR. Identification of amino acid determinants of the positional specificity of mouse 8S-lipoxygenase and human 15S-lipoxygenase-2. J Biol Chem 275:1287-1293, 2000
  92. Jisaka M, Boeglin WE, Kim RB, Brash AR. Site-directed mutagenesis studies on a putative fifth iron ligand of mouse 8S-lipoxygenase: retention of catalytic activity on mutation of serine-558 to asparagine, histidine, or alanine. Arch Biochem Biophys 386:136-142, 2001
  93. Krieg P, Marks F, Furstenberger G. A gene cluster encoding human epidermis-type lipoxygenases at chromosome 17p13.1: cloning, physical mapping, and expression. Genomics 73:323-330, 2001
  94. Kim E, Muga SJ, Fischer SM. Identification and characterization of a phorbol ester-responsive element in the murine 8S-lipoxygenase gene. J Biol Chem 279:11188-11197, 2004
  95. Goetzl EJ, Sun FF. Generation of unique mono-hydroxyeicosatetraenoic acids from arachidonic acid by human neutrophils. J Exp Med 150:406-411, 1979
  96. Rabinovitch H, Durand J, Gualde N, Rigaud M. Metabolism of polyunsaturated fatty acids by mouse peritoneal macrophages: the lipoxygenase metabolic pathway. Agents & Actions 11:580-583, 1981
  97. Capdevila J, Yadagiri P, Manna S, Falck JR. Absolute configuration of the hydroxyeicosatetraenoic acids (HETEs) formed during catalytic oxygenation of arachidonic acid by microsomal cytochrome P-450. Biochem Biophys Res Commun 141:1007-1011, 1986
  98. Jim K, Hassid A, Sun F, Dunn MJ. Lipoxygenase activity in rat kidney glomeruli, glomerular epithelial cell, and cortical tubules. J Biol Chem 257:10294-10299, 1982
  99. Camp RD, Mallet AI, Woollard PM, Brain SD, Black AK, Greaves MW. The identification of hydroxy fatty acids in psoriatic skin. Prostaglandins 26:431-447, 1983
  100. Hunter JA, Finkbeiner WE, Nadel JA, Goetzl EJ, Holtzman MJ. Predominant generation of 15-lipoxygenase metabolites of arachidonic acid by epithelial cells from human trachea. Proc Natl Acad Sci USA 82:4633-4637, 1985
  101. EI Attar, TMA, Lin HS, Vanderhoek JY. Biosynthesis of prostaglandins and hydroxy fatty acids in primary squamous carcinomas of head and neck in humans, Cancer Lett 27:255-259, 1985
  102. Yamada M, Proia AD. 8(S)-hydroxyeicosatetraenoic acid is the lipoxygenase metabolite of arachidonic acid that regulates epithelial cell migration in the rat cornea. Cornea 19(3 Suppl):S13-20, 2000
  103. Naito M, Chenicek KJ, Naito Y, DiGiovanni J. Susceptibility to phorbol ester skin tumor promotion in (C57BL/6 x DBN/2) F1 mice is inherited as an incomplete dominant trait: evidence for multi-locus involvement. Carcinogenesis 9:639-645, 1988
  104. Yamamoto S, Kiyoto I, Aizu E, Sasakawa N, Nakaki T, Kato R. Comparison of some biochemical properties of epidermis in tumor promotion-susceptible and -resistant strains of mice. Jpn J Pharmacol 47:45-49, 1988
  105. Fischer SM, Jasheway DW, Klann RC, Butler AP, Patrick KE, Baldwin JK, Cameron GS. Correlation of phorbol ester promotion in the resistant C57BL/6J mouse with sustained hyperplasia but not ornithine decarboxylase or protein kinase C. Cancer Res 49:6693-6699, 1989
  106. DiGiovanni J, Bhatt TS, Walker SE. C57BL/6 mice are resistant to tumor promotion by full thickness skin wounding. Carcinogenesis 14:319-321, 1993
  107. Nair J, Fursrenberger G, Burger F, Marks F, Bartsch H. Promutagenic etheno-DNA adducts in multistage mouse skin carcinogenesis: correlation with lipoxygenase-catalyzed arachidonic acid metabolism. Chern Res Toxicol 13:703-709, 2000
  108. Muller-Decker K, Scholz K, Marks F, Furstenberger G. Differential expression of prostaglandin H synthase isozymes during multistage carcinogenesis in mouse epidermis. Mol Carcinog 12:31-41, 1995
  109. Muga SJ, Thuillier P, Pavone A, Rundhaug JE, Boeglin WE, Jisaka M, Brash AR, Fischer SM. 8S-lipoxygenase products activate peroxisome proliferator-activated receptor a and induce differentiation in murine keratinocytes. Cell Growth & Differ 11:447-454, 2000
  110. Kim E, Rundhaug JE, Benavides F, Yang P, Newman RA, Fischer SM. An antitumorigenic role for murine 8S-lipoxygenase in skin carcinogenesis. Oncogene 24:1174-1187, 2005
  111. Brash AR, Boeglin WE, Chang MS. Discovery of a second 15S-lipoxygenase in humans. Proc Natl Acad Sci USA 94:6148-6152, 1997
  112. Shappell SB, Keeney DS, Zhang J, Page R, Olson SJ, Brash AR. 15-Lipoxygenase-2 expression in benign and neoplastic sebaceous glands and other cutaneous adnexa. J Invest Dermatol 117:36-43, 2001
  113. Huang JT, Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C, Witztum JL, Funk CD, Conrad D, Glass CK. Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature 400:378-382, 1999
  114. Shappell SB, Gupta RA, Manning S, Whitehead R, Boeglin WE, Schneider C, Case T, Price J, Jack GS, Wheeler TM, Matusik RJ, Brash AR, Dubois RN. 15S-Hydroxyeicosatetraenoic acid activates peroxisome proliferator-activated receptor gamma and inhibits proliferation in PC3 prostate carcinoma cells. Cancer Res 61:497-503, 2001
  115. Bhatia B, Maldonado CJ, Tang S, Chandra D, Klein RD, Chopra D, Shappell SB, Yang P, Newman RA, Tang DG. Subcellular localization and tumor-suppressive functions of 15-lipoxygenase 2 (15-LOX2) and its splice variants. J Biol Chem 278:25091-25100, 2003
  116. Shappell SB, Boeglin WE, Olson SJ, Kasper S, Brash AR. 15-lipoxygenase-2 (15-LOX-2) is expressed in benign prostatic epithelium and reduced in prostate adenocarcinoma. Am J Pathal 155:235-245, 1999
  117. Jack GS, Brash AR, Olson SJ, Manning S, Coffey CS, Smith JAJ. Shappell SB. Reduced 15-lipoxygenase-2 immunostaining in prostate adenocarcinoma: correlation with gwade and expession in high-rade prostatic intaepithelial noplaia. Hum Pathol 30:1146-1154, 2000
  118. Tang S, Bhatia B, Maldonado CJ, Yang P, Newman RA, Liu J, Chandra D, Traag J, Klein D, Fischer SM, Chopra D, Shen J, Zhau HE, Chung LW, Tang DG. Evidence that arachidonate 15-lipoxygenase 2 is a negative cell cycle regulator in normal prostate epithelial cells. J Biol Chem 277:16189-16201, 2002