Deutsches Krebsforschungszentrum 
German Cancer Resarch CenterLOX-DB - LipOXygenases DataBase
What are Lipoxygenases?
Lipoxygenases and
cancer research
Display all entries
Sequence Comparison
Blast Search
Search Literature
Search Literature (adv.)
Image Gallery

LOX and cancer

There is a steadily increasing evidence from animal models and clinical observations indicating that LOX and their products may play a role in tumor formation and cancer metastasis [1-4]. Recently the concept has been put forward that LOX activation may be involved in both pro- and antitumorigenic effects [5].

i) procarcinogenic effects:

Many data show a correlation between a high expression of different LOX-isoforms and the development of human and experimental tumors suggesting a procarcinogenic role.
High expression of 5-LOX was found in prostate, lung and other cancer cell lines [6, 7]. 5-LOX is overexpressed in human pancreatic cancer, and 5S-HETE formation or inhibition respectively promote or inhibit the growth of prostate cancer cells [8, 9]. 5-LOX inhibitors can inhibit growth of mouse colon adenocarcinoma cell lines in vitro and in vivo [10].
Overexpression of platelet-type12S-LOX has been found in a variety of tumors including breast, colorectal and prostate cancer [11, 12] and has been shown to be present in a number of prostate, melanoma and other cancer cell lines [13-15]. The degree of 12-LOX overexpression in human prostate cancer correlates with the tumor grade and stage [1]. Forced overexpression of 12-LOX in prostate cancer cells increased angiogenesis and growth of tumors in mice [16]. Inhibition of the 12-LOX pathway in prostate cancer cells has been shown to induce apoptosis [17].
Overexpression of 15-LOX-1 has been reported in human prostate tumors [18], and overexpression correlates with the tumor grade [19]. Other reports show overexpression of 15-LOX-1 in human colorectal tumors [20] and breast carcinoma cells [21]. Suppression of the LOX pathways has been found to inhibit tumor formation in animal models such as the initiation-promotion approach of mouse skin carcinogenesis [4]. Upon tumor induction in mouse skin the LOX isoforms 8S- LOX and platelet-type12S-LOX have been found to be aberrantly overexpressed in papillomas and squamous cell carcinomas, leading to an accumulation of the corresponding metabolites 8S- and 12S-HETE [22, 23]. Both LOX products have been shown to induce chromosomal damage in primary basal mouse keratinocytes [24, 25]. Moreover, targeted overexpression of 8S-LOX in mouse skin strongly increased malignant conversion of papillomas but had no effect on the generation of these benign tumors [26]. In addition, platelet-type 12S-LOX-deficient mice have been shown to be less sensitive for tumor induction according to the initiation-promotion protocol [27].

ii) anticarcinogenic effects:

Downregulation of distinct LOXs in the course of tumor development indicate that these isoforms may cause antitumorigenic rather than protumorigenic. 15-LOX-2 expression has been found to be reduced in prostate cancer and high-grade prostatic intraepithelial neoplasia [28, 29]. 15S-LOX-1 expression was also reduced in human colorectal cancer [30], although this observation was confounded by another report [20].

iii) antagonistic effects of LOX products

12S-HETE and 13S-HODE have been proposed to have opposite effects on tumorigenesis. 12S-HETE is thought to enhance carcinogenesis due to an up-regulation of tumor cell adhesion molecules [31, 32], a stimulation of angiogenesis [12] and of tumor cell spreading [33], and an inhibition of apoptosis [34]. In contrast, 13S-HODE is likely to have antitumorigenic effects due to an induction of apoptosis and cell cycle arrest [30, 35] and an induction of differentiation [36, 37]. Both metabolites exhibit antagonistic effects on experimental tumor induction in mouse skin. Arachidonic acid has been shown to have a protumorigenic activity that is inhibited by linoleic acid. Accordingly, 12S-HETE has been reported to stimulate keratinocyte proliferation and adhesion to fibronectin, and to inhibit terminal differentiation of keratinocytes [38, 39] whereas 13S-HODE was found to reverse epidermal hyperproliferation in the skin of guinea pigs [40], to counteract the inhibition of terminal differentiation by 12S-HETE, and to prevent keratinocyte adhesion to fibronectin [41].
Transgenic mice overexpressing epidermis-type 12S-LOX in skin at high level showed increased tumor response which was parralleled by strong accumulation of the archidonic acid metabolite 12-HETE, whereas low transgene expression resulted in a reduced tumor response paralleled by an upregulation of the leukocyte-type 12S-LOX and an accumulation of the linoleic acid product 13-HODE indicating a complex interaction between different LOX isoforms and opposite roles of arachidonic acid and linoleic acid metabolites in the modulation of epidermal carcinogenesis [42].
In prostate cancer cells 13-HODE, a 15-LOX-1 metabolite up-regulates MAPK and Akt pathways, whereas15-HETE, a 15-LOX-2 metabolite downregulates MAPK and Akt pathways indicating opposing effects of 15-LOX-1 [that isound to be overexpressed in prostate tumors] and 15-LOX-2 [found to be down regulated in prostate tumors] [43].


  1. Nie D, Che M, Grignon D, Tang K, Honn KV. Role of eicosanoids in prostate cancer progression.
    Cancer Metastasis Rev. 2001;20(3-4):195-206. (

  2. Honn KV, Tang DG, Gao X, Butovich IA, Liu B, Timar J, Hagmann W. 12-lipoxygenases and 12(S)-HETE: role in cancer metastasis.
    Cancer Metastasis Rev. 1994 Dec;13(3-4):365-96. (

  3. Kelavkar U, Glasgow W, Eling TE. The effect of 15-lipoxygenase-1 expression on cancer cells.
    Curr Urol Rep. 2002 Jun;3(3):207-14. (

  4. Marks F, Fürstenberger G. Cancer chemoprevention through interruption of multistage carcinogenesis. The lessons learnt by comparing mouse skin carcinogenesis and human large bowel cancer.
    Eur J Cancer. 2000 Feb;36(3):314-29. (

  5. Shureiqi I, Lippman SM. Lipoxygenase modulation to reverse carcinogenesis.
    Cancer Res. 2001 Sep 1;61(17):6307-12. (

  6. Anderson KM, Seed T, Vos M, Mulshine J, Meng J, Alrefai W, Ou D, Harris JE. 5-Lipoxygenase inhibitors reduce PC-3 cell proliferation and initiate nonnecrotic cell death.
    Prostate. 1998 Nov 1;37(3):161-73. (

  7. Avis IM, Jett M, Boyle T, Vos MD, Moody T, Treston AM, Martinez A, Mulshine JL. Growth control of lung cancer by interruption of 5-lipoxygenase-mediated growth factor signaling.
    J Clin Invest. 1996 Feb 1;97(3):806-13. (

  8. Ghosh J, Myers CE. Arachidonic acid stimulates prostate cancer cell growth: critical role of 5-lipoxygenase.
    Biochem Biophys Res Commun. 1997 Jun 18;235(2):418-23. (

  9. Ghosh J, Myers CE. Central role of arachidonate 5-lipoxygenase in the regulation of cell growth and apoptosis in human prostate cancer cells.
    Adv Exp Med Biol. 1999;469:577-82. (

  10. Hussey HJ, Tisdale MJ. Inhibition of tumour growth by lipoxygenase inhibitors.
    Br J Cancer. 1996 Sep;74(5):683-7. (

  11. Natarajan R, Esworthy R, Bai W, Gu JL, Wilczynski S, Nadler J. Increased 12-lipoxygenase expression in breast cancer tissues and cells. Regulation by epidermal growth factor.
    J Clin Endocrinol Metab. 1997 Jun;82(6):1790-8. (

  12. Nie D, Hillman GG, Geddes T, Tang K, Pierson C, Grignon DJ, Honn KV. Platelet-type 12-lipoxygenase in a human prostate carcinoma stimulates angiogenesis and tumor growth.
    Cancer Res. 1998 Sep 15;58(18):4047-51. (

  13. Timar J, Raso E, Honn KV, Hagmann W. 12-lipoxygenase expression in human melanoma cell lines.
    Adv Exp Med Biol. 1999;469:617-22. (

  14. Ding XZ, Kuszynski CA, El-Metwally TH, Adrian TE. Lipoxygenase inhibition induced apoptosis, morphological changes, and carbonic anhydrase expression in human pancreatic cancer cells.
    Biochem Biophys Res Commun. 1999 Dec 20;266(2):392-9. (

  15. Nappez C, Liagre B, Beneytout JL. Changes in lipoxygenase activities in human erythroleukemia (HEL) cells during diosgenin-induced differentiation.
    Cancer Lett. 1995 Sep 4;96(1):133-40. (

  16. Gao X, Grignon DJ, Chbihi T, Zacharek A, Chen YQ, Sakr W, Porter AT, Crissman JD, Pontes JE, Powell IJ, et al. Elevated 12-lipoxygenase mRNA expression correlates with advanced stage and poor differentiation of human prostate cancer.
    Urology. 1995 Aug;46(2):227-37. (

  17. Pidgeon GP, Kandouz M, Meram A, Honn KV. Mechanisms controlling cell cycle arrest and induction of apoptosis after 12-lipoxygenase inhibition in prostate cancer cells.
    Cancer Res. 2002 May 1;62(9):2721-7. (

  18. Kelavkar UP, Nixon JB, Cohen C, Dillehay D, Eling TE, Badr KF. Overexpression of 15-lipoxygenase-1 in PC-3 human prostate cancer cells increases tumorigenesis.
    Carcinogenesis. 2001 Nov;22(11):1765-73. (

  19. Kelavkar UP, Cohen C, Kamitani H, Eling TE, Badr KF. Concordant induction of 15-lipoxygenase-1 and mutant p53 expression in human prostate adenocarcinoma: correlation with Gleason staging.
    Carcinogenesis. 2000 Oct;21(10):1777-87. (

  20. Ikawa H, Kamitani H, Calvo BF, Foley JF, Eling TE. Expression of 15-lipoxygenase-1 in human colorectal cancer.
    Cancer Res. 1999 Jan 15;59(2):360-6. (

  21. Reddy N, Everhart A, Eling T, Glasgow W. Characterization of a 15-lipoxygenase in human breast carcinoma BT-20 cells: stimulation of 13-HODE formation by TGF alpha/EGF.
    Biochem Biophys Res Commun. 1997 Feb 3;231(1):111-6. (

  22. 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. 1995 Oct;14(2):118-29. (

  23. 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. 1999 Feb;24(2):108-17. (

  24. Petrusevska RT, Furstenberger G, Marks F, Fusenig NE. Cytogenetic effects caused by phorbol ester tumor promoters in primary mouse keratinocyte cultures: correlation with the convertogenic activity of TPA in multistage skin carcinogenesis.
    Carcinogenesis. 1988 Jul;9(7):1207-15. (

  25. Nair J, Furstenberger G, Burger F, Marks F, Bartsch H. Promutagenic etheno-DNA adducts in multistage mouse skin carcinogenesis: correlation with lipoxygenase-catalyzed arachidonic acid metabolism.
    Chem Res Toxicol. 2000 Aug;13(8):703-9. (

  26. Muga SJ, Kim EJ, Fischer SM. Regulation of 8S-lipoxygenase in mouse skin.
    Proc Am Assoc Cancer Res. 2000 41:84.

  27. Virmani J, Johnson EN, Klein-Szanto AJ, Funk CD. Role of 'platelet-type' 12-lipoxygenase in skin carcinogenesis.
    Cancer Lett. 2001 Jan 26;162(2):161-5. (

  28. 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 Pathol. 1999 Jul;155(1):235-45. (

  29. Jack GS, Brash AR, Olson SJ, Manning S, Coffey CS, Smith JA Jr, Shappell SB. Reduced 15-lipoxygenase-2 immunostaining in prostate adenocarcinoma: correlation with grade and expression in high-grade prostatic intraepithelial neoplasia.
    Hum Pathol. 2000 Sep;31(9):1146-54. (

  30. Shureiqi I, Wojno KJ, Poore JA, Reddy RG, Moussalli MJ, Spindler SA, Greenson JK, Normolle D, Hasan AA, Lawrence TS, Brenner DE. Decreased 13-S-hydroxyoctadecadienoic acid levels and 15-lipoxygenase-1 expression in human colon cancers.
    Carcinogenesis. 1999 Oct;20(10):1985-95. (

  31. Chopra H, Timar J, Chen YQ, Rong XH, Grossi IM, Fitzgerald LA, Taylor JD, Honn KV. The lipoxygenase metabolite 12(S)-HETE induces a cytoskeleton-dependent increase in surface expression of integrin alpha IIb beta 3 on melanoma cells.
    Int J Cancer. 1991 Nov 11;49(5):774-86. (

  32. Liu B, Khan WA, Hannun YA, Timar J, Taylor JD, Lundy S, Butovich I, Honn KV. 12(S)-hydroxyeicosatetraenoic acid and 13(S)-hydroxyoctadecadienoic acid regulation of protein kinase C-alpha in melanoma cells: role of receptor-mediated hydrolysis of inositol phospholipids.
    Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9323-7. (

  33. Tang DG, Tarrien M, Dobrzynski P, Honn KV. Melanoma cell spreading on fibronectin induced by 12(S)-HETE involves both protein kinase C- and protein tyrosine kinase-dependent focal adhesion formation and tyrosine phosphorylation of focal adhesion kinase (pp125FAK).
    J Cell Physiol. 1995 Nov;165(2):291-306. (

  34. Tang DG, Chen YQ, Honn KV. Arachidonate lipoxygenases as essential regulators of cell survival and apoptosis.
    Proc Natl Acad Sci U S A. 1996 May 28;93(11):5241-6. (

  35. Shureiqi I, Chen D, Lee JJ, Yang P, Newman RA, Brenner DE, Lotan R, Fischer SM, Lippman SM. 15-LOX-1: a novel molecular target of nonsteroidal anti-inflammatory drug-induced apoptosis in colorectal cancer cells.
    J Natl Cancer Inst. 2000 Jul 19;92(14):1136-42. (

  36. Kamitani H, Geller M, Eling T. Expression of 15-lipoxygenase by human colorectal carcinoma Caco-2 cells during apoptosis and cell differentiation.
    J Biol Chem. 1998 Aug 21;273(34):21569-77. (

  37. Hill EM, Eling T, Nettesheim P. Changes in expression of 15-lipoxygenase and prostaglandin-H synthase during differentiation of human tracheobronchial epithelial cells.
    Am J Respir Cell Mol Biol. 1998 May;18(5):662-9. (

  38. Leyton J, Lee ML, Locniskar M, Belury MA, Slaga TJ, Bechtel D, Fischer SM. Effects of type of dietary fat on phorbol ester-elicited tumor promotion and other events in mouse skin.
    Cancer Res. 1991 Feb 1;51(3):907-15. (

  39. Fischer SM, Hagerman RA, Li-Stiles E, Lo HH, Maldve RE, Belury MA, Locniskar MF. Arachidonate has protumor-promoting action that is inhibited by linoleate in mouse skin carcinogenesis.
    J Nutr. 1996 Apr;126(4 Suppl):1099S-1104S. (

  40. Miller CC, Ziboh VA. Induction of epidermal hyperproliferation by topical n-3 polyunsaturated fatty acids on guinea pig skin linked to decreased levels of 13-hydroxyoctadecadienoic acid (13-hode).
    J Invest Dermatol. 1990 Mar;94(3):353-8. (

  41. Hagerman RA, Fischer SM, Locniskar MF. Effect of 12-O-tetradecanoylphorbol-13-acetate on inhibition of expression of keratin 1 mRNA in mouse keratinocytes mimicked by 12(S)-hydroxyeicosatetraenoic acid.
    Mol Carcinog. 1997 Jul;19(3):157-64. (

  42. Müller 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. 2002 Aug 15;62(16):4610-6. (

  43. Hsi LC, Wilson LC, Eling TE. Opposing effects of 15-lipoxygenase-1 and -2 metabolites on MAPK signaling in prostate: alteration in PPARgamma.
    J Biol Chem. 2002 Aug 19 [epub ahead of print] (

Go to top of this page.