title: 12-lipoxygenases and 12(S)-HETE: role in cancer metastasis.
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.
authors.affiliation: Department of Radiation Oncology, Wayne State University, Detroit, MI 48202, USA.
authors.forename: K V
authors.initials: KV
authors.lastname: Honn
authors.forename: D G
authors.initials: DG
authors.lastname: Tang
authors.forename: X
authors.initials: X
authors.lastname: Gao
authors.forename: I A
authors.initials: IA
authors.lastname: Butovich
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Timar
authors.forename: W
authors.initials: W
authors.lastname: Hagmann
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000595:Amino Acid Sequence; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001483:Base Sequence; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis / Q000502:physiology*; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis / Q000235:genetics / Q000503:physiopathology*; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology; D017386:Sequence Homology, Amino Acid
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase