Formation and antiproliferative effect of prostaglandin E3 from eicosapentaenoic acid in human lung cancer cells

Yang, Peiying; Chan, Diana; Felix, Edward; Cartwright, Carrie; Menter, David G.; Madden, Timothy; Klein, Russell D.; Fischer, Susan M.; Newman, Robert A.

doi:10.1194/jlr.m300455-jlr200

Cited by 104 publications

(90 citation statements)

References 35 publications

(49 reference statements)

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“…EPA not only can replace arachidonic acid in phospholipid bilayers but is also a competitive inhibitor of COX, reducing the production of 2-series PGs and thromboxane, in addition to the 4-series leukotrienes (11,12). Recent studies have also shown that 3-and 5-series eicosanoids derived from EPA are either less biologically active or inactive compared with the former products and are thus considered to exert effects that are less inflammatory (10,13,39,40). Furthermore, Serhan (14,15,39,41,42) and co-workers have described a group of polyoxygenated DHA and EPA derivatives termed Resolvins that are produced enzymatically in various tissues.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Autoxidation Products of the ω-3 Fatty Acid Eicosapentaenoic Acid in Vitro and in Vivo

Yin

Brooks

Gao

et al. 2007

Journal of Biological Chemistry

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Increased intake of fish oil rich in the -3 fatty acids eicosapentaenoic acid (EPA, C20:5 -3) and docosahexaenoic acid (DHA, C22:6 -3) reduces the incidence of human disorders such as atherosclerotic cardiovascular disease. However, mechanisms that contribute to the beneficial effects of fish oil consumption are poorly understood. Mounting evidence suggests that oxidation products of EPA and DHA may be responsible, at least in part, for these benefits. Previously, we have defined the free radical-induced oxidation of arachidonic acid in vitro and in vivo and have proposed a unified mechanism for its peroxidation. We hypothesize that the oxidation of EPA can be rationally defined but would be predicted to be significantly more complex than arachidonate because of the fact that EPA contains an addition carbon-carbon double bond. Herein, we present, for the first time, a unified mechanism for the peroxidation of EPA. Novel oxidation products were identified employing state-ofthe-art mass spectrometric techniques including Ag ؉ coordination ionspray and atmospheric pressure chemical ionization mass spectrometry. Predicted compounds detected both in vitro and in vivo included monocylic peroxides, serial cyclic peroxides, bicyclic endoperoxides, and dioxolane-endoperoxides.

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Section: Discussionmentioning

confidence: 99%

Identification of Novel Autoxidation Products of the ω-3 Fatty Acid Eicosapentaenoic Acid in Vitro and in Vivo

Yin

Brooks

Gao

et al. 2007

Journal of Biological Chemistry

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“…EPA not only can replace arachidonic acid in phospholipid bilayers but is also a competitive inhibitor of cyclooxygenase, reducing the production of 2-series PGs and thromboxane, in addition to the 4-series leukotrienes. As noted, the 3-and 5-series eicosanoids (respec- tively) derived from EPA are either less biologically active or inactive as compared with the former products and are thus considered to exert effects that are less inflammatory (34,35). Further, Serhan and colleagues (14 -17) have described a group of polyoxygenated DHA and EPA derivatives termed resolvins that are produced in various tissues.…”

Section: Discussionmentioning

confidence: 99%

Formation of F-ring Isoprostane-like Compounds (F3-Isoprostanes) in Vivo from Eicosapentaenoic Acid

Gao¹,

Yin²,

Milne³

et al. 2006

Journal of Biological Chemistry

118

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Eicosapentaenoic acid (EPA, C20:5, -3) is the most abundant polyunsaturated fatty acid (PUFA) in fish oil. Recent studies suggest that the beneficial effects of fish oil are due, in part, to the generation of various free radical-generated non-enzymatic bioactive oxidation products from -3 PUFAs, although the specific molecular species responsible for these effects have not been identified. Our research group has previously reported that pro-inflammatory prostaglandin F 2 -like compounds, termed F 2 -isoprostanes (IsoPs), are produced in vivo by the free radical-catalyzed peroxidation of arachidonic acid and represent one of the major products resulting from the oxidation of this PUFA. Based on these observations, we questioned whether F 2 -IsoP-like compounds (F 3 -IsoPs) are formed from the oxidation of EPA in vivo. Oxidation of EPA in vitro yielded a series of compounds that were structurally established to be F 3 -IsoPs using a number of chemical and mass spectrometric approaches. The amounts formed were extremely large (up to 8.7 ؉ 1.0 g/mg EPA) and greater than levels of F 2 -IsoPs generated from arachidonic acid. We then examined the formation of F 3 -IsoPs in vivo in mice. Levels of F 3 -IsoPs in tissues such as heart are virtually undetectable at baseline, but supplementation of animals with EPA markedly increases quantities up to 27.4 ؉ 5.6 ng/g of heart. Interestingly, EPA supplementation also markedly reduced levels of pro-inflammatory arachidonate-derived F 2 -IsoPs by up to 64% ( p < 0.05). Our studies provide the first evidence that identify F 3 -IsoPs as novel oxidation products of EPA that are generated in vivo. Further understanding of the biological consequences of F 3 -IsoP formation may provide valuable insights into the cardioprotective mechanism of EPA.

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“…Syntheses of PGE 2 and PGE 3 are catalyzed by the same COX, but the biological effects of PGE 2 and PGE 3 are distinct. PGE 2 has been shown to promote cancer development (5-7), whereas PGE 3 has been recently found to have anticancer effects (9). Until recently, PGE 3 was an underappreciated and poorly understood eicosanoid because of the lack of sensitive and convenient methods for its measurement.…”

Section: Discussionmentioning

confidence: 99%

“…Metabolism of the n-6 AA (20:4n-6) and the n-3 EPA (20:5n-3) by the COX pathway produces PGs of two (e.g., PGE 2 ) and three series (e.g., PGE 3 ), respectively. These metabolites, PGE 2 and PGE 3 , have been shown to differently affect cancer growth (5)(6)(7)(8)(9). To determine the impact of the change in tissue ratio of n-6͞n-3 fatty acids as a result of fat-1 expression on the generation of the cancerrelated eicosanoids, we chose to measure the contents of PGE 2 and PGE 3 in melanoma and stromal tissues of fat-1 transgenic and WT mice by using lipid mediator lipidomics [liquid chromatography (LC)-UV-tandem MS (MS͞MS)].…”

Section: Differential Profiles Of Eicosanoids In B16 Melanoma and Strmentioning

confidence: 99%

“…The eicosanoids derived from omega-6 (n-6) and omega-3 (n-3) PUFAs are functionally distinct, and some have important opposing physiological functions (3,4). For example, AA-derived eicosanoids such as PGE 2 and leukotriene B 4 (LTB 4 ) have been shown to promote cancer formation, growth, and metastasis, whereas EPA-derived eicosanoids have suppressive effects (4)(5)(6)(7)(8)(9). Because eicosanoid precursors (i.e., AA and EPA) compete for the same metabolic enzymes [cyclooxygenase (COX) and lipoxygenase], the availability of AA and EPA and their ratio in cellular lipids determine the cell eicosanoid profile.…”

mentioning

confidence: 99%

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Melanoma growth is reduced in fat-1 transgenic mice: Impact of omega-6/omega-3 essential fatty acids

Xia

Lü

Wang

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

127

106

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An important nutritional question as to whether the ratio of omega-6 (n-6) to omega-3 (n-3) fatty acids plays a role in tumorigenesis remains to be clarified in well qualified experimental models. The recently engineered fat-1 mice, which can convert n-6 to n-3 fatty acids and have a balanced ratio of n-6 to n-3 fatty acids in their tissues and organs independent of diet, allow carefully controlled studies to be performed in the absence of potential confounding factors of diet and therefore are a useful model for elucidating the role of n-6͞n-3 fatty acid ratio in tumorigenesis. We implanted mouse melanoma B16 cells into transgenic and WT littermates and examined the incidence of tumor formation and tumor growth rate. The results showed a dramatic reduction of melanoma formation and growth in fat-1 transgenic mice. The level of n-3 fatty acids and their metabolite prostaglandin E 3 (PGE3) were much higher (but the n-6͞n-3 ratio is much lower) in the tumor and surrounding tissues of fat-1 mice than that of WT animals. The phosphatase and tensin homologue deleted on the chromosome 10 (PTEN) gene was significantly up-regulated in the fat-1 mice. In vitro experiments showed that addition of the n-3 fatty acid eicosapentaenoic acid or PGE3 inhibited the growth of B16 cell line and increased the expression of PTEN, which could be partially attenuated by inhibition of PGE3 production, suggesting that PGE3 may act as an antitumor mediator. These data demonstrate an anticancer (antimelanoma) effect of n-3 fatty acids through, at least in part, activation of PTEN pathway mediated by PGE3.prostaglandin E3 ͉ eicosapentaenoic acid ͉ tumorigenesis

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Formation and antiproliferative effect of prostaglandin E3 from eicosapentaenoic acid in human lung cancer cells

Cited by 104 publications

References 35 publications

Identification of Novel Autoxidation Products of the ω-3 Fatty Acid Eicosapentaenoic Acid in Vitro and in Vivo

Identification of Novel Autoxidation Products of the ω-3 Fatty Acid Eicosapentaenoic Acid in Vitro and in Vivo

Formation of F-ring Isoprostane-like Compounds (F3-Isoprostanes) in Vivo from Eicosapentaenoic Acid

Melanoma growth is reduced in fat-1 transgenic mice: Impact of omega-6/omega-3 essential fatty acids

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