Article

Cancer and Metastasis Reviews

, Volume 13, Issue 3, pp 365-396

First online:

12-Lipoxygenases and 12(S)-HETE: role in cancer metastasis

  • Kenneth V. HonnAffiliated withDivion of Cancer Biology, Department of Radiation Oncology, Wayne State UniversityDepartments of Chemistry, Wayne State UniversityDepartments of Pathology, Wayne State UniversityGershenson Radiation Oncology Center, Harper Hospital
  • , Dean G. TangAffiliated withDivion of Cancer Biology, Department of Radiation Oncology, Wayne State University
  • , Xiang GaoAffiliated withDivion of Cancer Biology, Department of Radiation Oncology, Wayne State University
  • , Igor A. ButovichAffiliated withDivion of Cancer Biology, Department of Radiation Oncology, Wayne State UniversityLaboratory for Chemical Enzymology, Institute of Bioorganic Chemistry
  • , Bin LiuAffiliated withDivion of Cancer Biology, Department of Radiation Oncology, Wayne State UniversityDepartment of Medicine, Division of Hematology/Oncology, Duke University
  • , Jozsef TimarAffiliated withDivion of Cancer Biology, Department of Radiation Oncology, Wayne State UniversityFirst Institute of Pathology and Experimental Cancer Research, Semmelweis Medical University
  • , Wolfgang HagmannAffiliated withDivion of Cancer Biology, Department of Radiation Oncology, Wayne State UniversityDeutsches Krebsforschungszentrum

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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.

Key words

eicosanoids 12-lipoxygenase metastasis adhesion 12(S)-HETE protein kinase C