12-lipoxygenases and 12(S)-HETE: Role in Cancer Metastasis

Cancer Metastasis Rev. 1994 Dec;13(3-4):365-96. doi: 10.1007/BF00666105.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
  • Amino Acid Sequence
  • Animals
  • Arachidonate 12-Lipoxygenase / genetics
  • Arachidonate 12-Lipoxygenase / metabolism
  • Arachidonate 12-Lipoxygenase / physiology*
  • Base Sequence
  • Humans
  • Hydroxyeicosatetraenoic Acids / biosynthesis
  • Hydroxyeicosatetraenoic Acids / physiology*
  • Molecular Sequence Data
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / physiopathology*
  • Neoplasms / enzymology
  • Neoplasms / pathology
  • Neoplasms, Experimental / enzymology
  • Neoplasms, Experimental / pathology
  • Sequence Homology, Amino Acid


  • Hydroxyeicosatetraenoic Acids
  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
  • Arachidonate 12-Lipoxygenase