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.

15(S)-Lipoxygenase-2 Mediates Arachidonic Acid-stimulated Adhesion of Human Breast Carcinoma Cells through the Activation of TAK1, MKK6, and p38 MAPK

“…Collectively, these studies suggest that a balance between the production of different eicosanoid metabolites is required to maintain normal cellular growth characteristics and that the alteration of this balance can have implications for neoplastic development (41). For example, 12(S)-HETE was shown to mediate the adhesion of B16 melanoma cells exposed to extracellular matrix following retraction of vascular endothelial cells by a mechanism that requires protein kinase C (42,43). Subsequently, 12(S)-HETE was shown to stimulate ␣ IIb ␤ 3 integrin activation and tumor cell spreading on fibronectin (44) as well as ␣ v ␤ 3 integrin activation and lung endothelial cell adhesion to vitronectin (45).…”

In vivo and in vitro biotransformation of the lithium salt of gamma-linolenic acid by three human carcinomas

“…Indeed, GLA has now been shown to restore defective E-cadherin function in human lung, colon, breast, melanoma and liver cancer cells, with a corresponding loss of invasiveness (Jiang et al, 1995). GLA or its metabolites were 18:3 (GLA) ongation ( AA, arachidonic acid (20:4,,6); 22:3,r6, direct elongation product of DGLA; ADA, adrenic acid (22:4,,6) effective in inhibiting enzymes associated with metastasis or closely correlated with metastatic potential such as urokinase (du Toit et al, 1994), 12-lipoxygenase (Honn et al, 1994;Ziboh, 1996) and 5-lipoxygenase (Ziboh, 1996). In addition, GLA inhibits cell-matrix interactions and so GLA exerts inhibitory effects at several stages in the multistep process of tumour formation and progression (Jiang et al, 1996).…”

Influence of omega-6 PUFA arachidonic acid and bone marrow adipocytes on metastatic spread from prostate cancer

“…The precise mechanism of this is unclear. Arachidonic acid exerts influence through its COX-2 and LOX metabolites, inducing malignant CaP proliferation (Hughes-Fulford et al, 2006), inhibiting apoptosis (Ghosh, 2004), inducing angiogenesis (Nie et al, 1998), and inducing disease progression (Honn et al, 1994;Norrish et al, 1999). Studies of the 5-LOX product, 5-HETE, show this is as a key regulator of tumour aggressiveness.…”