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.