Modulation of angiogenesis by ω-3 polyunsaturated fatty acids is mediated by cyclooxygenases

Abstract

The potential role of dietary fats in cancer is attracting considerable interest within the community. Both epidemiologic and experimental findings suggest that omega-3 polyunsaturated fatty acids (-3 PUFAs), which are almost absent from typical Western diets, exert protective effects against cancer progression, although the precise mechanism of this suppression remains unknown. One of the potential targets for -3 PUFAs in cancer suppression is angiogenesis, a process of new blood vessel formation within rapidly growing tumors. Here, we demonstrate that -6 PUFAs stimulate and -3 PUFAs inhibit major proangiogenic processes in human endothelial cells, including the induction of angiopoietin-2 (Ang2) and matrix metalloprotease-9, endothelial invasion, and tube formation, that are usually activated by the major -6 PUFA arachidonic acid. The cyclooxygenase (COX)-mediated conversion of PUFAs to prostanoid derivatives participated in modulation of the expression of Ang2. Thus, the -6 PUFA-derived prostaglandin E2 augmented, whereas the -3 PUFA-derived prostaglandin E3 suppressed the induction of Ang2 by growth factors. Our findings are consistent with the suggestion that PUFAs undergo biotransformation by COX-2 to lipid mediators that modulate tumor angiogenesis, which provides new insight into the beneficial effects of IntroductionInitial reports of the beneficial effects of long-chain omega-3 polyunsaturated fatty acids (-3 PUFAs) in human physiology occurred in the mid-1970s with observations that the dietary intake of fish-derived lipids correlated with decreased incidence of cardiovascular diseases and cancer. Thus, the lower incidence of cardiac diseases in the Inuit population has been attributed to the content of fish, which are high in -3 PUFAs, in the Inuit diet. 1 In another seminal study, Japanese women were found to have a lower risk of breast cancer compared with their counterparts in other developed countries. 2 When Japanese women migrated to countries with higher prevalence of breast cancer and adopted local diets, the incidence of disease more closely resembled that of the local population, thus indicating the importance of environmental factors. Rapidly, the interest of researchers focused on the possible protective effects of oily fish-derived -3 PUFAs, especially eicosapentaenoic acid (EPA; C20:5 n-3) and docosahexaenoic acid (DHA; C22:6 n-3). These -3 PUFAs are produced by phytoplankton and are accumulated in the fatty tissue of fish. -6 PUFAs, which are derived principally from animal fat and include arachidonic acid (AA; C20:4 n-6), and -3 PUFAs are both essential for mammals, since they cannot be synthesized and must be consumed in diet.The mechanistic information underpinning the inhibitory effects of -3 PUFA intake on disease development is deficient. Both -6 and -3 PUFAs have a number of critical homeostatic functions. 3 As constituents of structural phospholipids of the cell membrane they influence membrane fluidity, modulate intracellular signaling pathways, and modify cell-cell interacti...

Activation of Cytosolic Phospholipase A2 Downstream of the Src-Phospholipase D1 (PLD1)-Protein Kinase C γ (PKCγ) Signaling Axis Is Required for Hypoxia-induced Pathological Retinal Angiogenesis

“…In addition, other studies have reported that inhibition of either cPLA 2 or iPLA 2 prevents VEGF-induced EC proliferation, supporting a role for these PLA 2 in the modulation of angiogenesis (24,25). Moreover, the observations that whereas feeding mice a -3 PUFA-rich diet reduces angiogenesis, a -6 PUFA-rich diet enhances angiogenesis reinforce a role for PLA 2 in the regulation of angiogenesis (27,28).…”

“…Tube Formation Require cPLA 2 -mediated AA Release-Recent studies have suggested that PUFA such as AA play a role in the regulation of angiogenesis (27,28). Because cPLA 2 hydrolyzes glycerophospholipids with AA at the sn-2 position, we hypothesized that cPLA 2 -dependent AA release is required for pathological retinal angiogenesis.…”

“…By hydrolyzing glycerophospholipids that contain arachidonic acid (AA) at the sn-2 position, cPLA 2 liberates AA, a substrate for the cyclooxygenase, lipoxygenase, and epoxygenase pathways (26). Moreover, it has been found that whereas omega-3 polyunsaturated fatty acids (-3 PUFA) decrease angiogenesis, -6 PUFA enhance neovascularization (27,28). However, it was not known up to now how these various signaling events targeting membrane phospholipids are integrated in the mediation of angiogenesis.…”

Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis

“…A widely accepted theory to explain the health-promoting effects of omega-3 fatty acids is that they suppress the metabolism of omega-6 arachidonic acid (ARA) to form proangiogenic or proinflammatory eicosanoids or serve as alternative substrates to generate omega-3 lipid mediators with beneficial actions (9). Indeed, the metabolism of omega-3 fatty acids by cyclooxygenase (COX) and lipoxygenase (LOX) enzymes generates 3-series prostaglandins (10,11) and leukotrienes (12), as well as unique omega-3 autacoids such as resolvins and protectins (13), which have antiinflammatory or antiangiogenic effects.…”

Targeting Angiogenesis in Cancer Treatments: Where do we Stand?

“…Such process is producing three isoforms (VEGFA120, VEGFA164, and VEGFA188) all of them physiologically active. VEGF-A family binds to two tyrosine-kinase receptors: VEGF receptor 1 (VEGFR-1 also known as flt-1) and VEGF receptor 2 (VEGFR-2, also called KDR/Flk-1), which are expressed almost exclusively in endothelial cells (22,23). VEGF-A has been shown to be the necessary factor in angiogenesis induction.…”