title: Lipoxygenase metabolism: roles in tumor progression and survival.
abstract: The metabolism of arachidonic acid through lipoxygenase pathways leads to the generation of various biologically active eicosanoids. The expression of these enzymes vary throughout the progression of various cancers, and thereby they have been shown to regulate aspects of tumor development. Substantial evidence supports a functional role for lipoxygenase-catalyzed arachidonic and linoleic acid metabolism in cancer development. Pharmacologic and natural inhibitors of lipoxygenases have been shown to suppress carcinogenesis and tumor growth in a number of experimental models. Signaling of hydro[peroxy]fatty acids following arachidonic or linoleic acid metabolism potentially effect diverse biological phenomenon regulating processes such as cell growth, cell survival, angiogenesis, cell invasion, metastatic potential and immunomodulation. However, the effects of distinct LOX isoforms differ considerably with respect to their effects on both the individual mechanisms described and the tumor being examined. 5-LOX and platelet type 12-LOX are generally considered pro-carcinogenic, with the role of 15-LOX-1 remaining controversial, while 15-LOX-2 suppresses carcinogenesis. In this review, we focus on the molecular mechanisms regulated by LOX metabolism in some of the major cancers. We discuss the effects of LOXs on tumor cell proliferation, their roles in cell cycle control and cell death induction, effects on angiogenesis, migration and the immune response, as well as the signal transduction pathways involved in these processes. Understanding the molecular mechanisms underlying the anti-tumor effect of specific, or general, LOX inhibitors may lead to the design of biologically and pharmacologically targeted therapeutic strategies inhibiting LOX isoforms and/or their biologically active metabolites, that may ultimately prove useful in the treatment of cancer, either alone or in combination with conventional therapies.
authors.affiliation: Department of Clinical Surgery, Trinity College Dublin, St. James Hospital, Dublin 8, Ireland. pibgeong@tcd.ie
authors.forename: Graham P
authors.initials: GP
authors.lastname: Pidgeon
authors.forename: Joanne
authors.initials: J
authors.lastname: Lysaght
authors.forename: Sriram
authors.initials: S
authors.lastname: Krishnamoorthy
authors.forename: John V
authors.initials: JV
authors.lastname: Reynolds
authors.forename: Ken
authors.initials: K
authors.lastname: O'Byrne
authors.forename: Daotai
authors.initials: D
authors.lastname: Nie
authors.forename: Kenneth V
authors.initials: KV
authors.lastname: Honn
mesh_terms: D000818:Animals; D017209:Apoptosis; D016718:Arachidonic Acid / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D018450:Disease Progression; D006801:Humans; D007107:Immune System / Q000502:physiology; D008084:Lipoxygenase / Q000032:analysis / Q000502:physiology*; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000209:etiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology
chemical_list: D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases