Abstract
Arachidonic acid metabolites have been implicated in multiple steps of carcinogenesis. Their role in tumor cell metastasis, the ultimate challenge for the treatment of cancer patients, are however not well-documented. Arachidonic acid is primarily metabolized through three pathways, i.e., cyclooxygenase, lipoxygenase, and P450-dependent monooxygenase. In this review we focus our attention on one specific lipoxygenase, i.e., 12-lipoxygenase, and its potential role in modulating the metastatic process. In mammalian cells there exist three types of 12-lipoxygenases which differ in tissue distribution, preferential substrates, and profile of their metabolites. Most of these 12-lipoxygenases have been cloned and sequenced, and the molecular and biochemical determinants responsible for catalysis of specific substrates characterized. Solid tumor cells express 12-lipoxygenase mRNA, possess 12-lipoxygenase protein, and biosynthesize 12(S)-HETE [12(S)-hydroxyeicosatetraenoic acid], as revealed by numerous experimental approaches. The ability of tumor cells to generate 12(S)-HETE is positively correlated to their metastatic potential. A large collection of experimental data suggest that 12(S)-HETE is a crucial intracellular signaling molecule that activates protein kinase C and mediates the biological functions of many growth factors and cytokines such as bFGF, PDGF, EGF, and AMF. 12(S)-HETE plays a pivotal role in multiple steps of the metastatic ‘cascade’ encompassing tumor cell-vasculature interactions, tumor cell motility, proteolysis, invasion, and angiogenesis. The fact that 12-lipoxygenase is expressed in a wide diversity of tumor cell lines and 12(S)-HETE is a key modulatory molecule in metastasis provides the rationale for targeting these molecules in anti-cancer and anti-metastasis therapeutic protocols.
Similar content being viewed by others
References
Weiss L, Orr FW, Honn KV: Interactions between cancer and the microvasculature: a rate-regulator for metastasis. Clin Expl Metastasis 7: 127–167, 1989
Liotta LA: Tumor invasion and metastasis: Role of the extracellular matrix. Cancer Res 46: 1–7, 1986
Zetter BR: The cellular basis of site-specific tumor metastasis. N Engl J Med 322: 605–612, 1990
Nicolson GL: Tumor and host molecules important in the organ preference of metastasis. Seminars Cancer Biol 2: 143–154, 1991
Weinstat-Saslow D, Steeg PS: Angiogenesis and colonization in the tumor metastatic process: basic and applied advances. FASEB J 8: 401–407, 1994
Needleman P, Turk J, Jakschik BA, Morrison AR, Lefkowith JB: Arachidonic acid metabolism. Ann Rev Biochem 55: 69–102, 1986
Spector AA, Gordon JA, Moore SA: Hydroxyeicosate-traenoic acids (HETEs). Prog Lipid Res 27: 271–273, 1988
Serhan CN: Lipoxin biosynthesis and its impact in inflammatory and vascular events. Biochim Biophys Acta 1212: 1–25, 1994
Nicosia S, Patrono C: Eicosanoid biosynthesis and action: novel opportunities for pharmacological intervention. FASEB J 3: 1941–1948, 1989
Greenberg ER, Baron JA, Freeman DH, Jr., Mandel JS, Haile R: Reduced risk of large-bowel adenomas among aspirin users. J Natl Cancer Inst 85: 912–916, 1993
Felder CC, Ma LL, Liotta LA, Kohn EC: The antiproliferative and antimetastatic compound L651582 inhibits muscarinic acetylcholine receptor-stimulated calcium influx and arachidonic acid release. J Pharmacol Expl Ther 267: 967–971, 1991
Marnett LJ: Aspirin and the potential role of prostaglandins in colon cancer. Cancer Res 52: 5575–5589, 1992
Butcher RD, Wojcik SJ, Lints T, Wilson T, Schofield PC, Ralph R: Arachidonic acid, a growth signal in murine P815 mastocytoma cells. Cancer Res 53: 3405–3410, 1993
Honn KV, Cicone B, Skoff A: Prostacyclin, A potent antimetastatic agent. Science 212: 1270–1272, 1981
Honn KV, Tang DG, Chen YQ: Platelets and cancer metastasis: More than an epiphenomenon. Seminar Thromb Hemost 18: 392–415, 1993
Honn KV, Tang DG, Crissman JD: Platelets and cancer metastasis: A causal relationship? Cancer Metastasis Rev 11: 325–351, 1993
Chen YQ, Liu B, Tang DG, Honn KV: Fatty acid modulation of tumor cell-platelet-vessel wall interaction. Cancer Metastasis Rev 11: 389–410, 1993
Honn KV, Tang DG: Adhesion molecules and tumor cell interaction with endothelium and subendothelial matrix. Cancer Metastasis Rev 11: 353–375, 1992
Tang DG, Honn KV: Eicosanoids and tumor cell metastasis. In: Harris JE, Braun DP, Anderson KM (eds) Prostaglandin Inhibitors in Tumor Immunology and Immunotherapy. CRC press, Boca Raton, Ann Arbor, London, Tokyo, 1994, pp 73–108
Bastida E, Bertomeu MC, Haas TA, Almiral L, Lauri D, Orr FW, Buchanan MR: Regulation of tumor cell adhesion by intracellular 13-HODE:15HETE ratio. J Lipid Med 2: 281–293, 1990
Buchanan MR, Bastida E: Endothelium and underlying membrane reactivity with platelets, leukocytes and tumor cells: Regulation by the lipoxygenase-derived fatty acid metabolites, 13-HODE and HETE's. Med Hypothesis 27: 317–325, 1988
Funk CD: Molecular biology in the eicosanoid field. Prog Nuc Acid Res Mol Biol 45: 67–98, 1993
Takahashi Y, Ueda N, Yamamoto S: Two immunologically and catalytically distinct arachidonate 12-Lipoxygenases of bovine platelets and leukocytes. Arch Biochem Biophys 266: 613–621, 1988
Hansbrough JR, Takahashi Y, Ueda N, Yamamoto S, Holtzman MJ: Identification of a novel arachidonate 12-lipoxygenase in bovine tracheal epithelial cells distinct from leukocyte and platelet forms of the enzyme. J Biol Chem 265: 1771–1776, 1990
Yoshimoto T, Suzuki H, Yamamoto S, Takai T, Yokoyama C, Tanabe T: Cloning and sequence analysis of the cDNA for arachidonate 12-lipoxygenase of porcine leukocytes. Proc Natl Acad Sci USA 87: 2142–2146, 1990
De Marzo N, Sloane DL, Dicharry S, Highland E, Sigal E: Cloning and expression of an airway epithelial 12-lipoxygenase. Am J Physiol 262: L198-L207, 1992
Sigal E, Craik CS, Highland E, Grunberger D, Costello LL, Dixon RAF, Nadel JA: Molecular cloning and primary structure of human 15-lipoxygenase. Biochem Biophys Res Commun 157: 457–464, 1988
O'Prey J, Chester J, Thiele BJ, Janetzki S, Prehn S, Fleming J, Harrison PR: Promoter structure and complete sequence of the gene encoding the rabbit erythroid cell-specific 15-lipoxygenase. Gene 84: 493–499, 1989
Dixon RAF, Jones RE, Diehl RE, Bennett CD, Kargman S, Rouzer CA: Cloning of the cDNA for human 5-lipoxygenase. Pro Natl Acad Sci USA 85: 416–420, 1988
Balcarek JM, Theisen TW, Cook MN, Varrichio A, Hwang S, Strohsacker MW, Crooke ST: Isolation and characterization of a cDNA clone encoding rat 5-lipoxygenase. J Biol Chem 263: 13937–13941, 1988
Funk CD, Furci L, Fitzgerald GA: Molecular cloning, primary structure, and expression of the human platelet/erythroleukemia cell 12-lipoxygenase. Proc Natl Acad Sci USA 87: 5638–5642, 1990
Watanabe S, Medina JF, Haeggstrom JZ, Radmark O, Samuelsson B: Molecular cloning of a 12-lipoxygenase cDNA from rat brain. Eur J Biochem 212: 605–612, 1992
Izumi T, Hoshiko S, Radmark O, Samuelsson B: Cloning of the cDNA for human 12-lipoxygenase. Proc Natl Acad Sci USA 87: 7477–7481, 1990
Sloane DL, Craik SS, Sigal E: The expression of active human reticulocyte 15-lipoxygenase in bacteria. Biochim Biophys Acta 49: S11-S16, 1990
Funk CD, Funk LB, FitzGerald GA, Samuelsson B: Characterization of human 12-lipoxygenase genes. Proc Natl Acad Sci USA 89: 3962–3966, 1992
Funk CD, Furchi L, Fitzgerald GA: Adv Prostaglandin Thromboxane Leukotriene Res 21: 33, 1990
Hada T, Ueda N, Takahashi Y, Yamamoto S: Catalytic properties of human platelet 12-lipoxygenase as compared with the enzymes of other origins. Biochim Biophys Acta 1083: 89, 1991
Kuhn H, Sprecher H, Brash AR: On singular and dual positional specificity of lipoxygenases. J Biol Chem 265: 16300–16306, 1990
Boyington JC, Gaffney BJ, Amzel GLM: The three-dimensional structure of an arachidonic acid 15-lipoxygenase. Science 260: 1482–1486, 1993
Chen X-S, Kurre U, Jenkins NA, Copeland NG, Funk CD: cDNA cloning, expression, mutagenesis of C-terminal isoleucine, genomic structure, and chromosomal localization of murein 12-lipoxygenases. J Biol Chem 269: 13979–13987, 1994
Fleming J, Thiele BJ, Chester J, O'Prey J, Janetzki S, Aitken A, Anton IA, Rapoport SM, Harrison PR: The complete sequence of the rabbit erythroid cell-specific 15-lipoxygenase mRNA: comparison of the predicted amino acid sequence of the erythrocyte lipoxygenase with other lipoxygenases. Gene 79: 18–188, 1989
Sloane DL, Leung R, Craik CS, Sigal E: A primary determinate for lipoxygenase positional specificity. Nature 354: 149–152, 1991
Matsumoto T, Funk CD, Radmark O, Hoog JO, Jornavall H, Samuelsson B: Molecular cloning and amino acid sequence of human 5-lipoxygenase. Proc natl Acad Sci USA 85: 26–30, 1988
Nguyen T, Falgueyret J-P, Abramovitz M, Riendeau D: Evaluation of the role of conserved His and Met residues among lipoxygenases by site-directed mutagenesis of recombinate human 5-lipoxygenase. J Biol Chem 266: 22057–22062, 1991
Zhang YY, Radmark O, Samuelson B: Mutagenesis of some conserved residues in human 5-lipoxygenase: Effects on enzyme activity. Proc Natl Acad Sci USA 89: 485–489, 1992
Yoshimoto T, Arakaws T, Hada T, Yamamoto S, Takahashi E: Structure and chromosomal localization of human arachidonate 12-lipoxygenase gene. J Biol Chem 267: 24805–14809, 1992
Arakawa T, Oshima T, Kishimoto K, Yoshimoto T, Yamamoto S: Molecular structure and function of the porcine arachidonate 12-lipoxygenase gene. J Biol Chem 267: 12188–12191, 1992
Chang W-C, Liu Y-W, Ning C-C, 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
Chang W-C, Ning C-C, Lin MT, Huang J-D: Epidermal growth factor enhances a microsomal 12-lipoxygenase activity in A431 cells. J Biol Chem 267: 3657–3666, 1992
Funk CD, Fitzgerald GA: Eicosanoid forming enzyme mRNA in human tissues. Analysis by quantitative polymerase chain reaction. J Biol Chem 266: 12508–12513, 1991
Natarajan R, Gu J-L, Rossi J, Gonzales N, Lanting L, Xu L, Nadler J: Elevated glucose and angiotensin II increase 12-lipoxygenase activity and expression in porcine aortic smooth muscle cells. Proc Natl Acad Sci USA 90: 4947–4951, 1993
Faisst S, Meyer S: Compilation of vertebrate-encoded transcription factors. Nucl Acids Res 20: 3–26, 1992
Chen YQ, Duniec ZM, Liu B, Hagmann W, Gao X, Shimoji K, Marnett LJ, Johnson CR, Honn KV: Endogenous 12(S)-HETE production by tumor cells and its role in metastasis. Cancer Res 54: 1574–1579, 1994
Glasgow WC, Eling TE: Epidermal growth factor regulation of linoleic acid metabolism in syrian hamster embryo fibroblasts. In: Nigam S, Honn KV, Marnett LJ, Walden T (eds) Eicosnois and other Bioactive Lipids in Cancer Inflammation and Radiation Injury. Kluwer Academic Publishers, 1992, pp 467–470
Hussain H, Shornick JP, Shannon VR, Wilson JD, Funk CD, Pentland AP, Holtzman MJ: Epidermis contains platelet-type 12-lipoxygenase that is overexpressed in germinal layer keratinocytes in psoriasis. Am J Physiol 266: C243-C253, 1994
Chen X-S, Funk CD: Structure-function properties of human platelet 12-lipoxygenase: Chimeric enzyme andin vitro mutagenesis studies. FASEB J 7: 694–701, 1993
Kuhn H, Heydeck D, Sprecher H: On the mechanistic reasons for the dual positional specificity of the reticulocyte lipoxygenase. Biochim Biophys Acta 830: 25–29, 1985
Gardner HW: Soybean lipoxygenase-1 enzymically forms both (9S)- and (13S)-hydroperoxides from linoleic acid by pH-dependent mechanism. Biochim Biophys Acta 1001: 274–281, 1989
Kuhn H, Heydeck D, Wiesner R, Schewe T: The positional specificity of wheat lipoxygenase. The carboxylic group as signal for the recognition of the hydrogen removal. Biochim Biophys Acta 830: 25–29, 1985
Rapoport S, Hartel B, Hausdorf G: Methionine sulfoxide formation: the cause of self-inactivation of reticulocyte lipoxygenase. Eur J Biochem 139: 573–576, 1984
Zakut R, Grossman S, Pinsky A, Wilchek M: Evidence for an essential methionine residue in lipoxygenase. FEBS Letters 71: 107–110, 1976
Watanabe T, Haeggstrom JZ: Rat 12-lipoxygenase: mutations of amino acids implicated in positional specificity of 15- and 12-lipoxygenases. Biochem Biophys Res Commun 192: 1023–1029, 1993
Yamamoto S: Mammalian lipoxygenases: molecular structures and functions. Biochim Biophys Acta 1128: 117–131, 1992
Toh H, Yokoyama C, Tanabe T, Yoshimoto T, Yamamoto S: Molecular evolution of cyclooxygenase and lipoxygenase. Prostaglandins 44: 291–315, 1992
Sigal E: The molecular biology of mammalian arachidonic acid metabolism. Amer J Physiol 4(1): L13-L28, 1991
Kroneck PMH, Cucurou C, Ullrich V, Ueda N, Suzuki H, Yoshimoto T, Matsuda S, Yamamoto S: Porcine leukocyte 5- and 12-lipoxygenases are iron enzymes. FEBS Letters 286: 105–107, 1991
Schilstra MJ, Veldink GA, Vliegenthart JFG: Kinetic analysis of the induction period in lipoxygenase catalysis. Biochem 32: 7686–7691, 1993
Aoshima H, Kajiwara T, Hatanaka A, Nakatani H, Hiromi K: Modification of lipoxygenase by hydrogen peroxide and photooxidation. Int J Pept Protein Res 10: 219–225, 1977
Butovich IA: Aerobic catalytic cycle of 5-lipoxygenase: a new interpretation of the enzyme activation by synthetic and natural amphiphilic acids. In: The Proceedings for the Third International Conference on Lipid Mediators in Health and Disease. Jerusalem, Israel. 1993, pp 121
Feiters MC, Boelens H, Veldink GA, Vliegenthart JFG, Navaratnam S, Allen JC, Nolting H-F, Hermes C: X-Ray absorption spectroscopic studies on iron in soybean lipoxygenase: a model for mammalian lipoxygenases. Recl Trav Chim Pays Bas 109: 133–146, 1990
Nelson MJ, Seitz SP, Cowling RA: Enzyme-bound pentadienyl and peroxyl radicals in purple lipoxygenase. Biochem 29: 6897–6903, 1990
Veldink GA, Vliegenthart JFG, Boldingh G: Plant lipoxygenases. Prog Fat Other Lipids 15: 131–166, 1977
Bryant RW, Schewe T, Rapoport SM, Bailey JM: Leukotriene formation by a purified reticulocyte lipoxygenase enzyme. Conversion of arachidonic acid and 15-hydroperoxyeicosatetraenoic acid to 14,15-leukotriene A4. J Biol Chem 260: 3548–3555, 1985
Cucurou C, Battioni JP, Daniel R, Mansuy D: Peroxidaselike activity of lipoxygenases: different substrate specificity of potato-5 lipoxygenase and soybean 15-lipoxygenase, and particular activity of vitamine E derivatives for the 5-lipoxygenase. Biochim Biophys Acta 1081: 95–105, 1991
Kuhn H, Eggert L, Zabolotsky OA, Myagkova G, Schewe T: Keto fatty acids not containing doubly allylic methylenes and lipoxygenase substrates. Biochemistry 30: 10269–10273, 1991
Funk MO, Jr., Andre JC, Otsuki T: Oxygenation of trans polyunsaturated fatty acids by lipoxygenase reveals steric features of the catalytic mechanism. Biochem 26: 6880–6889, 1987
Salzmann U, Kuhn H, Schewe T, Rapoport SM: Pentane formation during the anaerobic reaction of reticulocyte lipoxygenase. Comparison with lipoxygenases from soybeans and green pea seeds. Biochim Biophys Acta 795: 535–542, 1984
Takahashi Y, Reddy GR, Ueda N, Yamamoto S, Arase S: Arachidonate 12-lipoxygenase of platelet-type in human epidermal cells. J Biol Chem 268: 16443–16448, 1993
Mahmud I, Suzuki T, Yamamoto Y, Suzuki H, Takahashi Y, Yoshimoto T, Yamamoto S: Induction of cyclooxygenase and suppression of 12-lipoxygenase in human erythroleukemia cells upon phorbol ester-induced differentiation. Biochim Biophys Acta 1166: 211–216, 1993
Siegel MI, McConnell RT, Porter NA, Cuatrecasas P: Arachidonate metabolism via lipoxygenase and 12L-hydroperoxy-5, 8, 10, 14-icosatetraenoic acid peroxidase sensitive to anti-inflammatory drugs. Proc Natl Acad Sci USA 77: 308–312, 1980
Yoshimoto T, Miyamoto Y, Ochi K, Yamamoto S: Arachidonate 12-lipoxygenase of porcine leukocyte with activity for 5-hydroxyeicosatetraenoic acid. Biochem Biophys Acta 713: 638–646, 1982
Marnett LJ, Leithauser MT, Richards KM, Blair I, Honn KV, Yamamoto S, Yoshimoto T: Arachidonic acid metabolism of cytosolic fractions of Lewis Lung carcinoma cells. Adv Prostaglandin Thromboxane Leukotriene Res 21: 895–900, 1990
Shornick LP, Holtzman MJ: A cryptic, microsomal-type arachidonate 12-lipoxygenase is tonically inactivated by oxidation-reduction conditions in cultured epithelial cells. J Biol Chem 268: 371–376, 1993
Hagmann W, Kagawa D, Renaud C, Honn KV: Activity and protein distribution of 12-lipoxygenase in HEL cells: Induction of membrane-association by phorbol ester TPA, modulation of activity by glutathione and 13-HPODE, and Ca2+-dependent translocation to membranes. Prostaglandins 46: 471–477, 1993
Hagmann W, Maher R, Honn KV: Intracellular distribution, activity, and Ca2+-dependent translocation of 12-lipoxygenase in Lewis lung tumor cells. In: Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury (K.V. Honn, L.J. Marnett, S. Nigam, eds), Kluwer Academic Press, in Press, 1994
Baba A, Sakuma S, Okamoto H, Inoue T, Iwata H: Calcium induces membrane translocation of 12-lipoxygenase in rat platelets. J Biol Chem 264: 15790–15795, 1989
Liu B, Timar J, Howlett J, Diglio CA, Honn KV: Lipoxygenase metabolites of arachidonic and linoleic acids modulate the adhesion of tumor cells to endothelium via regulation of protein kinase C. Cell Regul 2: 1045–1055, 1991
Schonhardt T, Ferber E: Translocation of phospholipase A2 from cytosol to membranes induced by 1-oleoyl-2-acetyl-glycerol in serum-free cultured macrophages. Biochem Biophys Res Commun 149: 769–775, 1987
Balsinde J, Diez E, Mollinedo F: Arachidonic acid release from diacylglycerol in human neutrophils. J Biol Chem 266: 15638–15643, 1991
Rouzer CA, Kargman S: Translocation of 5-lipoxygenase to the membrane in human leukocytes challenged with ionophore A23187. J Biol Chem 263: 10980–10988, 1988
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 skinin vivo. J Biol Chem 266: 15738–15745, 1991
Clark JD, Lin LL, Kriz RW, Ramesha CS, Sultzman LA, Lin AY, Milona N, Knopf JL: A novel arachidonic acidselective cytosolic PLA2 contains a Ca2+-dependent translocation domain with homology to PKC and GAP. Cell 65: 1043–1051, 1991
Hadjiagapiou C, Spector AA: 12-hydroxyeicosatetraenoic acid reduces prostacyclin production by endothelial cells. Prostaglandins 31: 1135–1144, 1986
Sekiya F, Takagi J, Usui T, Kawajiri K, Kobayashi Y, Sato F, Saito Y: 12S-hydroxyeicosatetraenoic acid plays a central role in the regulation of platelet activation. Biochem Biophys Res Commun 179: 345–351, 1991
Hofer G, Bieglmayer CH, Kopp B, Janisch H: Measurement of eicosanoids in menstrual fluid by the combined use of high pressure chromatography and radioimmunoassay. Prostaglandins 45: 413–426, 1993
Wetzka B, Schafer W, Scheibel M, Nusing R, Zahradnik HP: Eicosanoid production by intrauterine tissues before and after labor in short-term tissue culture. Prostaglandins 45: 571–581, 1993
Liu B, Marnett LJ, Chaudhary A, Ji C, Blair IA, Johnson CR, Diglio CA, Honn KV: Biosynthesis of 12(S)-hydroxyeicosatetraenoic acid by B16 amelanotic melanoma cells is a determinant of their metastatic potential. Lab Invest 70: 314–323, 1994
Honn KV, Tang D, Grossi I, Duniec ZM, Timar J, Renaud C, Leithauser M, Blair I, Johnson CR, Diglio CA, Kimler VA, Taylor JD, Marnett LJ: Tumor cell-derived 12(S)-Hydroxyeicosatetraenoic acid induces microvascular endothelial cell retraction. Cancer Res 54: 565–574, 1994
Honn KV, Nelson KK, Renaud C, Bazaz R, Diglio CA, Timar J: Fatty acid modulation of tumor cell adhesion to microvessel endothelium and experimental metastasis. Prostaglandins 44: 413–429, 1992
Honn KV, Tang DG, Grossi IM, Renaud C, Duniec ZM, Johnson CR, Diglio CA: Enhanced endothelial cell retraction mediated by 12(S)-HETE: A proposed mechanism for the role of platelets in tumor cell metastasis. Exp Cell Res 210: 1–9, 1994
Pauli BU, Augustin-Voss HG, El-Sabban ME, Johnson RC, Hammar DA: Organ preference of metastasis: the role of endothelial cell adhesion molecules. Cancer Metastasis Rev 9: 175–189, 1990
Ruoslahti E, Giancotti FG: Integrins and tumor cell dissemination. Cancer Cells 4: 119–126, 1989
Singer IJ, Scott S, Kawka DW, Kazazis DM: Adhesosomes: specific granules containing receptors for laminin, c3bi, fibrinogen, fibronectin and vitronectin in human polymorphonuclear leukocytes and monocytes. J Cell Biol 109: 3169–3182, 1989
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 αIIbβ3 on melanoma cells. Int J Cancer 49: 774–786, 1991
Zachary I, Rozengurt E: Focal adhesion kinase (p125FAK): A point of convergence in the action of neuropeptides, integrins, and oncogenes. Cell 71: 891–894, 1992
Schaller MD, Borgman CA, Cobb BS, Vines RR, Reynolds AB, Parsons TJ: pp125FAK, a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc Natl Acad Sci USA 89: 5192–5196, 1992
Guan J-L, Shalloway D: Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature 358: 690–692, 1992
Grossi IM, Fitzgerald LA, Umbarger LA, Nelson KK, Diglio CA, Taylor JD, Honn KV: Bidirectional control of membrane expression and/or activation of the tumor cell IRGpIIb/IIIa receptor and tumor cell adhesion by lipoxygenase products of arachidonic and linoleic acid. Cancer Res 49: 1029–1037, 1989
Chang YS, Chen YQ, Timar J, Grossi IM, Fitzgerald LA, Diglio CA, Honn KV: Increased expression of αIIβb3 integrin in subpopulations of murine melanoma cells with high lung-colonizing ability. Int J Cancer 51: 445–454, 1992
Chen YQ, Gao X, Timar J, Tang D, Grossi IM, Chelladurai M, Kunicki TJ, Fligiel SEG, Taylor JD, Honn KV: Identification of the αIIbβ3 integrin in murine tumor cells. J Biol Chem 267: 17314–17320, 1992
Chopra H, Timar J, Rong X, Grossi IM, Hatfield JS, Fligiel SEG, Finch CA, Taylor JD, Honn KV: Is there a role for the tumor cell integrin αIIβ3 and cytoskeleton in tumor cellplatelet interaction? Clin Expl Metastasis 10: 125–138, 1992
Timar J, Chen YQ, Liu B, Bazaz R, Taylor JD, Honn KV: The lipoxygenase metabolite 12(S)-HETE promotes αIIbβ3 integrin-mediated tumor cell spreading on fibronectin. Int J Cancer 52: 594–603, 1992
Stoker M, Gherardi E: Regulation of cell movement: the motility cytokines. Biochim Biophys Acta 1072: 81–102, 1991
Liotta LA, Mandler R, Murano G, Katz DA, Gordon RK, Chiang PK, Schiffman E: Tumor-cell autocrine motility factor. Proc Natl Acad Sci USA 83: 3302–3306, 1986
Watanabe H, Carmi P, Hogan V, Raz T, Silletti S, Nabi IR, Raz A: Purification of human tumor cell autocrine motility factor and molecular cloning of its receptor. J Biol Chem 266: 13442–13448, 1991
Timar J, Silletti S, Bazaz R, Raz A, Honn KV: Regulation of melanoma-cell motility by the lipoxygenase metabolite 12(S)-HETE. Int J Cancer 55: 1003–1010, 1993
Silletti S, Raz A: Autocrine motility factor (AMF) is a growth factor. Biochem Biophys Res Commun 194: 446–457, 1993
Liu B, Maher RJ, Hannun YA, Porter AT, Honn KV: 12(S)-HETE increases the invasive potential of prostate tumor cells through selective activation of PKCα. J Natl Cancer Inst 86: 1145–1151, 1994
Honn KV, Timar J, Rozhin J, Bazaz R, Sameni M, Ziegler G, Sloane BF: A lipoxygenase metabolite, 12-(S)-HETE, stimulates protein kinase C-mediated release of cathepsin B from malignant cells. Exp Cell Res 214: 120–130, 1994
Schmitt M, Graff JH: Tumor-associated proteases. Fibrinolysis 6: 3–26, 1992
Sloane BF, Moin K, Krepela E, Rozhin J: Cathepsin B and its endogenous inhibitors: the role in tumor cell malignancy. Cancer Metastasis Rev 9: 333–352, 1990
Sloane BF, Moin K, Sameni M, Tait LR, Rozhin J, Ziegler J: Membrane association of cathepsin B can be induced by transfection of human breast epithelial cells with c-Ha-ras oncogene. J Cell Sci 107: 373–384, 1994
Sloane BF, Rozhin J, Johnson K, Taylor H, Crissman JD, Honn KV: Cathepsin B: association with plasma membrane in metastatic tumors. Proc Natl Acad Sci USA 83: 2483–2487, 1986
Sloane BF, Rozhin JR, Gomez AP, Grossi IM, Honn KV: Effects of 12-hydroxyeicosatetraenoic acid on release of cathepsin B and cysteine proteinase inhibitors from malignant melanoma cells. In: Honn KV, Marnett LJ, Nigam S, Walden TL (eds) Eicosanoids and other Bioactive Lipids in Cancer and Radiation Injury. Kluwer, Boston, 1991, pp 373–377
Timar J, Tang D, Bazaz R, Haddard MM, Kimler VA, Taylor JD, Honn KV: PKC mediates 12(S)-HETE-induced cytoskeletal rearrangement in B16a melanoma cells. Cell Motil Cytoskel 26: 49–65, 1993
Tang DG, Honn KV: Role of protein kinase C and phosphatases in 12(S)-HETE-induced tumor cell cytoskeletal reorganization. In: Honn KV, Marnett LJ, Nigam S (eds) Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation and Radiation Injury. Kluwer, Boston, 1994, in press
Crissman JD, Hatfield J, Schadenbrand M, Sloane BF, Honn KV: Arrest and extravasation of B16 amelanotic melanoma in murine lungs. A light and electron microscopic study. Lab Invest 53: 470–478, 1985
Chew EC, Cheung SL:In vitro studies on the invasion of blood vessel by choriocarcinoma cells. Anticancer Res 9: 133–139, 1989
Kramer RH, Nicolson GL: Interactions of tumor cells with vascular endothelial cell monolayers: a model for metastatic invasion. Proc Natl Acad Sci USA 76: 5704–5708, 1979
Huang AJ, Silverstein SC: Mechanisms of neutrophil migration across endothelial cells. In: Simionescue N, Siminonescu M (eds) Endothelial Cell Dysfunctions. Plenum Press, New York, 1992, pp 201–231
Lafrenie R, Shaughnessy S, Orr FW: Cancer cell interactions with injured or activated endothelium. Cancer Metastasis Rev 11: 377–388, 1992
Nicholson GL, Custead SE, Dulski KM, Milas L: Effect of gamma irradiation on cultured rat and mouse microvessel endothelial cells: metastatic tumor cell adhesion, subendothelial matrix degradation, and secretion of tumor cell growth factors. Clin Exp Metastasis 9: 457–468, 1991
Honn KV, Grossi IM, Diglio CA, Wotjukiewicz M, Taylor JD: Enhanced tumor cell adhesion to the subendothelial matrix resulting from 12(S)-HETE-induced endothelial cell retraction. FASEB J 3: 2285–2293, 1989
Grossi IM, Diglio CA, Honn KV: Control of tumor cell induced endothelial cell retraction by lipoxygenase metabolites, prostacyclin and prostacyclin analogs. In: Honn KV, Marnett LJ, Nigam S, Walden T (eds) Eicosanoids and Other Bioactive Lipids in Cancer and Radiation Injury. Kluwer Academic Publishers, Boston, 1991, pp 409–414
Tang DG, Diglio CA, Honn KV: 12(S)-HETE-induced microvascular endothelial cell retraction results from PKC-dependent rearrangement of cytoskeletal elements and αvβ3 integrins. Prostaglandins 45: 249–268, 1993
Tang DG, Chen YQ, Diglio CA, Honn KV: PKC-dependent effects of 12(S)-HETE on endothelial cell vitronectin receptor and fibronectin receptor. J Cell Biol 121: 689–704, 1993
Tang DG, Timar J, Grossi IM, Renaud C, Kimler VA, Diglio CA, Taylor JD, Honn KV: The lipoxygenase metabolite, 12(S)-HETE, induces a protein kinase C-dependent cytoskeletal rearrangement and retraction of microvascular endothelial cells. Exp Cell Res 207: 361–375, 1993
El-Sabban M, Pauli BU: Cytoplasmic dye transfer between metastatic tumor cells and vascular endothelium. J Cell Biol 115: 1375–1382, 1991
Wysolmersky RB, Lagunoff D: Inhibition of endothelial cell retraction by ATP depletion. Am J Pathol 132: 28–37, 1988
Laposata M, Dovnasky DK, Shen HS: Thrombin-induced gap formation in confluent endothelial cell monolayers. Blood 62: 549–556, 1983
Wysolmersky RB, Lagunoff D: Involvement of myosin light chain kinase in endothelial cell retraction. Proc Natl Acad Sci USA 87: 16–20, 1990
Tang DG, Diglio CA, Honn KV: 12(S)-HETE-induced microvascular endothelial cell retraction is mediated by cytoskeletal rearrangement dependent on PKC activation. In: Nigam S, Honn KV, Marnett LJ, Walden T (eds) Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation and Radiation Injury. Kluwer Academic Publishers, Boston, 1992, pp 219–229
Albelda SM, Mueller WA, Buck CA, Newman PJ: Molecular and cellular properties of PECAM-1 (endoCAM/CD31): A novel vascular cell-cell adhesion molecule. J Cell Biol 114: 1059–1068, 1991
Newman PJ, Berndt MC, Gorski J, White GC, Lyman S, Paddock C, Mueller WA: PECAM-1 (CD31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily. Science 247: 1219–1222, 1990
Tang DG, Chen YQ, Newman PJ, Shi L, Gao X, Diglio CA, Honn KV: Identification of PECAM-1 in solid tumor cells and its potential involvement in tumor cell adhesion to endothelium. J Biol Chem 268: 22883–22894, 1993
Tang DG, Grossi IM, Chen YQ, Diglio CA, Honn KV: 12(S)-HETE promotes tumor cell adhesion by increasing surface expression of αvβ3 integrins on endothelial cells. Int J Cancer 54: 102–111, 1993
Tang DG, Diglio CA, Honn KV: Activation of microvascular endothelium by eicosanoid 12(S)-hydroxyeicosatetraenoic acid leads to enhanced tumor cell adhesion via up-regulation of surface expression of αvβ3 integrin: A posttranscriptional, protein kinase C- and cytoskeleton-dependent process. Cancer Res 54: 1119–1129, 1994
Hamberg M, Samuelsson B: Prostaglandin endoperoxides. Novel transformation of arachidonic acid in human platelets. Proc Natl Acad Sci USA 71: 3400–3404, 1974
Setty BNY, Dubowy RL, Stuart MJ: Endothelial cell proliferation may be mediated via the production of endogenous lipoxygenase metabolites. Biochem Biophys Res Commun 144: 345–351, 1987
Axelrod J, Burch RM, Jelsema C: Receptor-mediated activation of phospholipase A2 via GTP-binding proteins: archidonic acid and its metabolite as second messengers. TINS 11: 106–113, 1988
Perlman MB, Johnson A, Jubiz W, Malik AB: Lipoxygenase products induce neutrophil activation and increase endothelial permeability after thrombin-induced pulmonary microembolism. Circulation Res 64: 62–73, 1989
Rozengurt E: A role of arachidonic acid and its metabolites in the regulation of p21ras activity. Cancer Cells 3: 397–398, 1991
Hannigan GE, Williams BRG: Signal transduction by interferon-α through arachidonic acid metabolism. Science 251: 204–207, 1991
Smith RJ, Justen JM, Nidy EG, Sam LM, Bleasdale JE: Transmembrane signaling in human polymorphonuclear neutrophils: 15(S)-hydroxy-(5Z, 8Z, 11Z, 13E)-eicosatetraenoic acid modulates receptor agonist-triggered cell activation. Proc Natl Acad Sci USA 90: 7270–7274, 1993
Han JW, McCormick F, Macara IG: Regulation of RasGAP and the neurofibromatosis-1 gene product by eicosanoids. Science 252: 576–579, 1991
Valles J, Santos MT, Marcus AJ, Safier JB, Broekman MJ, Islam N, Ullman HL, Aznar J: Downregulation of human platelet reactivity by neutrophils: Participation of lipoxygenase derivatives and adhesive proteins. J Clin Invest 92: 1357–1365, 1993
Peppelenbosch MP, Tertoolen LGJ, Hage WJ, de Laat SW: Epidermal growth factor-induced actin remodeling is regulated by 5-lipoxygenase and cyclooxygenase products. Cell 74: 565–575, 1993
Kim JA, Gu J, Natarajian R, Berliner JA, Nadler J: Evidence that a leukocyte type of 12-lipoxygenase is expressed in normal human vascular and mononuclear cells. Clin Res 41: 148A, 1993
Piomelli D, Volterra A, Dale N, Siegelbaum SA, Kandel ER, Schwartz JH, Belardetti F: Lipoxygenase metabolites of arachidonic acid as second messengers for presynaptic inhibition of Aplysia sensory cells. Nature 328: 38–43, 1987
Nadler JL, Natarajian R, Stern N: Specific action of the lipoxygenase pathway in mediating angiotensin II-induced aldosterone synthesis in isolated adrenal glomerula cells. J Clin Invest 80: 1763–1769, 1987
Chan CC, Duhamel L, Ford-Hutchison A: Leukotriene B4 and 12-hydroxyeicosatetraenoic acid stimulate epidermal proliferationin vivo in the guinea pig. J Invest Dermatol 85: 333–334, 1985
Glasgow WC, Afshari CA, Barret JC, Eling TE: Modulation of the epidermal growth factor mitogenic response by metabolites of linoleic and arachidonic acid in Syrian hamster embryo fibroblasts. Differential effects in tumor suppressor (+) and (−) phenotypes. J Biol Chem 267: 10771–10779, 1992
Antonipillai I: 12-lipoxygenase products are potent inhibitors of prostacyclin-induced renin release. Proc Soc Exp Biol Med 194 224–230, 1990
Etingin OR, Hajjar DP: Evidence for cytokine regulation of cholesterol metabolism in herpes virus-infected arterial cells by the lipoxygenase pathway. J Lipid Res 31: 299–305, 1990
Setty BN, Graeber JE, Stuart MJ: The mitogenic effect of 15- and 12-hydroxyeicosatetraenoic acid on endothelial cells may be mediated via diacylglycerol kinase. J Biol Chem 262: 17613–17622, 1987
Dethlefsen SM, Shepro D, D'Amore P: Arachidonic acid metabolites in bFGF-, PDGF-, and serum-stimulated vascular cell growth. Exp Cell Res 212: 262–273, 1994
O'Brian CA, Ward NE: Biology of the protein kinase C family. Cancer Metastasis Rev 8: 199–214, 1989
Liu B, Renaud C, Nelson KK, Chen YQ, Bazaz R, Kowynia J, Timar J, Diglio CA, Honn KV: Protein kinase C inhibitor calphostin C reduces B16 amelanotic melanoma cell adhesion to endothelium and lung colonization. Int J Cancer 52: 147–152, 1992
Gopalakrishina R, Barsky SH: Tumor-promoter-induced membrane-bound protein kinase C regulates hematogenous metastasis. Proc Natl Acad Sci USA 85: 612–616, 1988
Dekker LV, Parker PJ: Protein kinase C - a question of specificity. TIBS 19: 73–77, 1994
Borner C, Guadagno SN, Hsiao WWL, Fabbro D, Barr M, Weinstein IB: Expression of four protein kinase C isoforms in rat fibroblasts. Differential alterations in ras-, src-, and fos-transformed cells. J Biol Chem 267: 12900–12910, 1992
Chun JS, Jacobson BS: Spreading of HeLa cells on a collagen substratum requires a second messenger formed by the lipoxygenase metabolism of arachidonic acid released by collagen receptor clustering. Mol Biol Cell 3: 481–492, 1992
Chun JS, Jacobson BS: Requirement for diacylglycerol and protein kinase C in HeLa cell-substratum adhesion and their feedback amplification of arachidonic acid production for optimum cell spreading. Mol Biol Cell 4: 271–281, 1993
Hagerman RA, Smith TJ, Locniskar MF: Lipoxygenase metabolites activate protein kinase C. FASEB J 7: A601, 1993
Natarajan R, Lanting L, Nadler XJ: Role of specific isoforms of protein kinase C in angiotensin II and lipoxygenase action in rat adrenal glomerulosa cells. Mol Cell Endocrinol 101: 59–66, 1994
Berridge MJ, Irvine RF: Inositol phosphates and cell signaling. Nature 341: 197–205, 1989
Cho Y, Ziboh VA: 13-hydroxyoctadecaenoic acid reverses epidermal hyperproliferation via selective inhibition of protein kinase C-β activity. Biochem Biophys Res Commun 201: 257–265, 1994
Gardiner PJ: Classification of protanoid receptors. Adv Prostaglandin Thromboxane Leukotriene Res 20: 110–118, 1990
Namba T, Oida H, Sugimoto Y, Kakizuka A, Negishi M, Ichikawa A, Narumiya S: cDNA cloning of a mouse prostacyclin receptor. Multiple signaling pathways and expression in thymic medulla. J Biol Chem 269: 9986–9992, 1994
Bastien L, Sawyer N, Grygorczk R, Metters KM, Adam M: Cloning, functional expression, and characterization of the human prostaglandin E2 receptor EP2 subtype. J Biol Chem 269: 11873–11877, 1994
Boie Y, Rushmore T, Darmon-Goodwin A, Grygorczk R, Slipetz DM, Metters KM, Abramovitz M: Cloning and expression of a cDNA for the human prostanoid IP receptor. J Biol Chem 269: 12173–12178, 1994
Gross E, Ruzicka T, Restorff BV, Stolz W, Klotz K-N: High-affinity binding and lack of growth-promoting activity of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) in a human epidermal cell line. J Invest Dermatol 94: 446–451, 1990
Croset M, Lagarde M: Stereospecific inhibition of PGH2induced aggregation by lipoxygenase products of eicosaenoic acids. Biochem Biophys Res Commun 112: 878–883, 1983
Fonlupt P, Croset M, Lagarde M: 12(S)-HETE inhibits the binding of PGH2/TXA2 receptor ligands in human platelets. Thromb Res 63: 239–248, 1991
Herbertsson H, Hammarstrom S: High-affinity binding sites for 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12(S)-HETE) in carcinoma cells. FEBS Lett 298: 249–252, 1992
Herbertsson H, Hammarstrom S: Cytosolic 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid binding sites in carcinoma cells. In: Honn KV, Marnett LJ, Nigam S (eds) Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation and Radiation Injury. Kluwer, Boston, 1994, in press
Kohn EC, Liotta LA: Invasion and metastasis: An old problem with new approaches. Oncology 7: 47–52, 1993
Kohn EC, Sandeen MA, Liotta LA:In vivo efficacy of a novel inhibitor of selected signal transduction pathways including calcium, arachidonate, and inositol phosphates. Cancer Res 52: 3208–3212, 1992
Hagmann W, Gao X, Timar J, Chen YQ, Fahrenkopf C, Kagawa D, Lee M, Zacharek A, Honn KV: Intracellular localization, activity, and bidirectional modulation of 12-lipoxygenase in A431 epidermoid carcinoma cells: Influence of epidermal growth factor, starvation, and inhibition of protein tyrosine kinase. Submitted
Silletti S, Timar J, Honn KV, Raz A: Autocrine motility factor induces 12-lipoxygenase expression and activity in high- but not low-metastatic murine melanoma cells. Cancer Res, 1994, in press
Eggens I, Fenderson BA, Toyokuni T, Dean B, Stroud MR, Hakomori S: Specific interaction between Lex and Lex determinants: a possible basis for cell recognition in preimplantation embryos and in embryonal carcinoma cells. J Biol Chem 264: 9476–9484, 1989
Hakomori S: New directions in cancer therapy based on abrrant expression of glycosphingolipids: anti-adhesion and ortho-signaling therapy. Cancer Cells 3: 461–470, 1991
Liu B, Khan WA, Hannun YA, Bazaz R, Renaud C, Stojakovic S, Timar J, Taylor J, Honn KV: 12(S)-HETE and 13(S)-HODE regulation of protein kinase C alpha in melanoma cells: Role of receptor mediated hydrolysis of inositol phospholipids. Submitted
Liu B, Honn KV: unpublished observations
Tang DG, Honn KV: 12-Lipoxygenase, 12(S)-HETE, and Cancer Metastasis. Annals New York Acad Sci 1994, in press
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Honn, K.V., Tang, D.G., Gao, X. et al. 12-Lipoxygenases and 12(S)-HETE: role in cancer metastasis. Cancer Metast Rev 13, 365–396 (1994). https://doi.org/10.1007/BF00666105
Issue Date:
DOI: https://doi.org/10.1007/BF00666105