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

Abstract

We investigated the formation and pharmacology of prostaglandin E3 (PGE3) derived from fish oil eicosapentaenoic acid (EPA) in human lung cancer A549 cells. Exposure of A549 cells to EPA resulted in the rapid formation and export of PGE3. The extracellular ratio of PGE3 to PGE2 increased from 0.08 in control cells to 0.8 in cells exposed to EPA within 48 h. Incubation of EPA with cloned ovine or human recombinant cyclooxygenase 2 (COX-2) resulted in 13- and 18-fold greater formation of PGE3, respectively, than that produced by COX-1. Exposure of A549 cells to 1 μM PGE3 inhibited cell proliferation by 37.1% (P < 0.05). Exposure of normal human bronchial epithelial (NHBE) cells to PGE3, however, had no effect. When A549 cells were exposed to EPA (25 μM) or a combination of EPA and celecoxib (a selective COX-2 inhibitor), the inhibitory effect of EPA on the growth of A549 cells was reversed by the presence of celecoxib (at both 5 and 10 μM). This effect appears to be associated with a 50% reduction of PGE3 formation in cells treated with a combination of EPA and celecoxib compared with cells exposed to EPA alone.These data indicate that exposure of lung cancer cells to EPA results in a decrease in the COX-2-mediated formation of PGE2, an increase in the level of PGE3, and PGE3-mediated inhibition of tumor cell proliferation. We investigated the formation and pharmacology of prostaglandin E3 (PGE3) derived from fish oil eicosapentaenoic acid (EPA) in human lung cancer A549 cells. Exposure of A549 cells to EPA resulted in the rapid formation and export of PGE3. The extracellular ratio of PGE3 to PGE2 increased from 0.08 in control cells to 0.8 in cells exposed to EPA within 48 h. Incubation of EPA with cloned ovine or human recombinant cyclooxygenase 2 (COX-2) resulted in 13- and 18-fold greater formation of PGE3, respectively, than that produced by COX-1. Exposure of A549 cells to 1 μM PGE3 inhibited cell proliferation by 37.1% (P < 0.05). Exposure of normal human bronchial epithelial (NHBE) cells to PGE3, however, had no effect. When A549 cells were exposed to EPA (25 μM) or a combination of EPA and celecoxib (a selective COX-2 inhibitor), the inhibitory effect of EPA on the growth of A549 cells was reversed by the presence of celecoxib (at both 5 and 10 μM). This effect appears to be associated with a 50% reduction of PGE3 formation in cells treated with a combination of EPA and celecoxib compared with cells exposed to EPA alone. These data indicate that exposure of lung cancer cells to EPA results in a decrease in the COX-2-mediated formation of PGE2, an increase in the level of PGE3, and PGE3-mediated inhibition of tumor cell proliferation. Prostaglandins, which are generated by cyclooxygenase (COX) metabolism of arachidonic acid (AA), play a pivotal role in maintaining cell development and homeostasis of various diseases, especially inflammation and cancer [as reviewed in ref. (1Dubois R.N. Abramson S.B. Crofford L. Gupta R.A. Simon L.S. Van De Putte L.B.A. Lipsky P.E. Cyclooxygenase in biology and disease.FASEB J. 1998; 12: 1063-1073Crossref PubMed Scopus (2198) Google Scholar)]. In contrast to a large body of evidence indicating that ω-6 polyunsaturated fatty acids such as AA promote the growth of tumor cells, ω-3 fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] have actually been shown to inhibit tumor cell proliferation [as reviewed in ref. (2Bartsch H. Nair J. Owen R.W. Dietary polyunsaturated fatty acids and cancers of the breast and colorectum: emerging evidence for their role as risk modifiers.Carcinogenesis. 1999; 20: 2209-2218Crossref PubMed Scopus (402) Google Scholar)]. Epidemiologic studies have shown an inverse relationship between blood levels of n-3 fatty acids derived from fish oils and the risk of prostate and lung cancers (3Terry P. Lichtenstein P. Feychting M. Ahlbom A. Wolk A. Fatty fish consumption and risk of prostate cancer.Lancet. 2001; 357: 1764-1766Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 4Takezaki T. Hirose K. Inoue M. Hamajima N. Yatabe Y. Mitsudomi T. Sugiura T. Kuroishi T. Tajima K. Dietary factors and lung cancer risk in Japanese: with special reference to fish consumption and adenocarcinomas.Br. J. Cancer. 2001; 84: 1199-1206Crossref PubMed Scopus (78) Google Scholar, 5Zhang J. Temme E.H. Kesteloot H. Fish consumption is inversely associated with male lung cancer mortality in countries with high levels of cigarette smoking or animal fat consumption.Int. J. Epidemiol. 2000; 29: 615-621Crossref PubMed Scopus (29) Google Scholar). However, molecular mechanisms for the pharmacologic anticancer activity of EPA have not been fully elucidated. A number of studies have suggested that the anticancer activities of both EPA and DHA are associated with their ability to inhibit the synthesis of 2-series prostaglandins, especially prostaglandin E2 (PGE2) production [as reviewed in ref. (6Rose D.P. Connolly J.M. Omega-3 fatty acids as cancer chemopreventive agents.Pharmacol. Ther. 1999; 83: 218-238Crossref Scopus (515) Google Scholar)]. In contrast to DHA, however, EPA can actually function as a substrate for COX and result in the synthesis of unique 3-series prostaglandin compounds (7Needleman P. Raz A. Minkes M.S. Ferrendelli J.A. Specher H. Triene prostaglandins: prostacyclin and thromboxane biosynthesis and unique biological properties.Proc. Natl. Acad. Sci. USA. 1979; 23: 1005-1014Google Scholar). To date, studies reporting the formation of 3-series prostaglandins by EPA have been performed using normal cells or tissues (8Spector A.A. Kaduce T.L. Figard P.H. Norton K.C. Hoak J.C. Czervionke R.L. Eicosapentaenoic acid and prostacyclin production by cultured human endothelial cells.J. Lipid Res. 1983; 24: 1595-1604Abstract Full Text PDF PubMed Google Scholar, 9Kulkarni P.S. Srinivasan B.D. Eicosapentaenoic acid metabolism in human and rabbit anterior uvea.Prostaglandins. 1986; 31: 1158-1164Crossref Scopus (22) Google Scholar). Fischer and Weber (10Fischer S. Weber P.C. Prostaglandin I3 is formed in vivo in man after dietary eicosapentaenoic acid.Nature. 1984; 4: 743-755Google Scholar), for example, provided the first evidence of in vivo formation of thromboxane A3 and prostaglandin I3 in humans fed fish oil. In addition, studies conducted in humans have shown that PGE3 levels increased by ∼10-fold in urine after ingestion of cod liver oil (40 ml/day) for 12 weeks (11Fischer S. Schacky C.V. Schweer H. Prostaglandins E3 and F3α are excreted in human urine after ingestion of n-3 polyunsaturated fatty acids.Biochim. Biophys. Acta. 1988; 963: 501-508Crossref PubMed Scopus (27) Google Scholar). In contrast to PGE2, the biological activity of PGE3 has received little attention. The effect of PGE3 on cell growth has been reported only in normal murine mammary epithelial (12McKenzie K.E. Bandyopadhyay G.K. Imagawa W. Sun K. Nandi S. ω-3 and ω-6 fatty acids and PGE2 stimulate the growth of normal but not tumor mouse mammary epithelial cells: evidence for alterations in the signaling pathways in tumor cells.Prostaglandins Leukot. Essent. Fatty Acids. 1994; 51: 437-443Abstract Full Text PDF PubMed Scopus (13) Google Scholar) and 3T3 fibroblast cells (13Bagga D. Wang L. Farias-Eisner R. Glaspy J.A. Reddy S.T. Differential effects of prostaglandin derived from ω-6 and ω-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion.Proc. Natl. Acad. Sci. USA. 2003; 100: 1751-1756Crossref PubMed Scopus (515) Google Scholar). Both studies showed that PGE2 and PGE3 stimulated the growth of normal cells but that PGE3 was much less potent than PGE2. A more recent study has suggested that PGE3, unlike PGE2, is not mitogenic to 3T3 fibroblasts (13Bagga D. Wang L. Farias-Eisner R. Glaspy J.A. Reddy S.T. Differential effects of prostaglandin derived from ω-6 and ω-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion.Proc. Natl. Acad. Sci. USA. 2003; 100: 1751-1756Crossref PubMed Scopus (515) Google Scholar). To date, however, the ability of cancer cells or even purified COX enzymes to form PGE3 from EPA has not been evaluated. Furthermore, the biochemical pharmacology of PGE3 in human cancer cells has not been investigated. In consideration of the documented higher level of expression of COX-2 in tumor cells than in normal cells (14Hasturk S. Kemp B. Kalapurakal S.K. Kurie J.M. Honh W.K. Lee of and in bronchial and cell lung PubMed Scopus Google Scholar), to the of human lung cancer A549 cells as as cloned to form PGE3 using EPA as a the effects of PGE2 and PGE3 on human lung cancer cell and the of PGE3 as an in in tumor cell In that the level of PGE3 was increased after A549 cells to The ability of cloned human recombinant COX-2 to form PGE3 from EPA was much greater than that of In contrast to PGE2, PGE3 inhibited the growth of human lung tumor cells but not normal human bronchial epithelial (NHBE) cells. In addition, PGE3 the effect of PGE2 on cancer cell Furthermore, the inhibitory effect of EPA on the growth of A549 cells was by celecoxib and 10 and effect was with a formation of PGE3 in cells. PGE2, PGE3, and were from of and were from PGE2 and PGE3 were in and to cell a We from were from were cell lung cancer A549 cells and cells were in A549 cells were cultured in with and cells were in bronchial epithelial cell growth A549 cells were in in and were to were with and treated with EPA AA or EPA AA μM in with μM for or 48 h. To the formation of PGE3 from cells were exposed to μM EPA and for and 48 h. The was and cells were by and to prostaglandin The production of PGE2 or PGE3 by cloned or COX-2 or human enzymes was by of 10 or μM AA or respectively, with enzymes in 5 2 and 1 μM The was by the of 1 acid of prostaglandins were to the of P. T. Fischer R.A. of and 3-series prostaglandins in cultured tumor PubMed Scopus Google Scholar). cell were with 2 of and in of (40 of 1 5 of and of as an were to the cell or Prostaglandins were with 2 of The were and to a of were performed of were in of by Prostaglandins in the cell were using a of 10 of and of were to 1 of cell The was to a that had been with and Prostaglandins were with 1 of The was a of and the was in of The prostaglandins were by the by P. T. Fischer R.A. of and 3-series prostaglandins in cultured tumor PubMed Scopus Google Scholar). was performed using a with an The prostaglandins were using a 2 The of 10 and The was and were the were using and of the for PGE2, for PGE3, and for of compounds was performed using as the a cell of The effects of PGE2 and PGE3 on cell proliferation were by the of R. B. M. D. Prostaglandin E2 a for cancer growth and PubMed Scopus Google Scholar). A549 and cells were in their for in to were for their in the of 1 of was to cells were with with and with and was and COX-2 expression in cells treated with EPA or AA was by were using and The in the was using a A of of was in of for 5 and on a to COX-2 purified was as the were a and to were in in were with or COX-2 for were for 1 with The were by the and exposed to was using various or of or The was performed using the which is and by within cells. The that is by cells and cells in the of When is in the of cell cells to were in and with μM EPA or and and celecoxib and 10 μM) and various of EPA and or celecoxib for h. were with and in for and were by using an on an with a was using a with were as a control for and as a control for as a control had and to in a and was to the between various a of < was The anticancer effect of EPA has been to the inhibition of COX activity and levels of PGE2 both in and in vivo of prostaglandin biosynthesis by eicosapentaenoic 1979; Full Text PDF PubMed Scopus Google Scholar, J. De of an eicosapentaenoic and docosahexaenoic acid on a human lung in PubMed Scopus Google Scholar). We have shown that a level of EPA μM) Glaspy J.A. Reddy S.T. D. D. D. of polyunsaturated with dietary fish oils in with prostate 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) results in more than a 50% reduction in PGE2 formation in lung cancer cells P. T. Fischer R.A. of and 3-series prostaglandins in cultured tumor PubMed Scopus Google Scholar). EPA is a substrate for COX (7Needleman P. Raz A. Minkes M.S. Ferrendelli J.A. Specher H. Triene prostaglandins: prostacyclin and thromboxane biosynthesis and unique biological properties.Proc. Natl. Acad. Sci. USA. 1979; 23: 1005-1014Google Scholar), the of lung cancer cells to form PGE3 from the ω-3 fatty acid When A549 cells were exposed to EPA and μM) for 48 the of PGE3 in the cell increased to as high as cells compared with that in the control < This increase of extracellular PGE3 was When A549 cells were exposed to μM EPA for 48 the extracellular ratio of PGE3 to PGE2 increased from 0.08 in control cells to 0.8 in treated cells The increase in the ratio of PGE3 PGE2 was shown in exposure of A549 cells to μM EPA for resulted in a rapid increase in extracellular PGE3 from cells in control cells to cells in treated cells. with EPA for the level of PGE3 increased from cells in control cells to cells in treated cells, the extracellular level of PGE3 cells. These data that A549 human lung cancer cells are to and export high of PGE3. The extracellular level of PGE3 after which by 48 levels of PGE3 had by 50% from the We the production of PGE3 in A549 cells was the result of or both enzymes cells both and COX-2 M. J. L. Y. S. M. M. cell lung cancer is by 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). ovine and human recombinant COX-2 were to for the formation of PGE2 or PGE3 using AA and respectively, as shown in both and COX-2 enzymes produced PGE2 with using 10 μM AA as a a reported by N. M. Fatty acid substrate of human and Full Text Full Text PDF PubMed Scopus Google Scholar, Differential inhibition of prostaglandin by and Full Text PDF PubMed Google Scholar). In the formation of PGE3 from EPA was greater with COX-2 than with 10 μM the of the enzymes using substrate to form PGE3 was human recombinant COX-2 ovine COX-2 ovine the production of PGE2 was and higher with both and COX-2 respectively, than the production of PGE3 by The ability of A549 cells to form PGE2 from AA exposed to EPA was The level of PGE2 in cells treated with both AA and EPA μM by in with that in cells treated with AA μM). was that the formation of PGE3 was in cells treated with EPA μM) or with AA EPA μM the levels of PGE3 increased after A549 cells were exposed to the data suggested to that the expression of COX-2 be the of EPA and AA to COX-2 A549 cells were exposed to μM EPA for and and of COX-2 was by the expression of COX-2 was not increased h. that of exposure of cells to EPA (25 and μM) COX-2 expression in A549 cells in a DHA and AA μM) the expression of COX-2 in A549 cells. of however, was not not To that PGE3 was generated by cloned enzymes or by cancer cells, the formation of PGE3 by EPA in the presence of a selective COX-2 or a selective in A549 cells was and 10 μM) PGE3 levels to and cells, respectively, from the control cell level of cells (P < 0.05). The inhibition of PGE3 formation by celecoxib in A549 cells was In to a to inhibit of activity Y. J. A. K. P.C. of in Natl. Acad. Sci. USA. 1998; PubMed Scopus Google Scholar), had no effect on the production of PGE3 by EPA We the inhibitory effect of celecoxib on PGE3 formation with cloned COX-2 enzymes and that celecoxib μM) inhibited the production of PGE3 by EPA by not The expression of COX-2 in cells in the presence of celecoxib was cells were exposed to both EPA and the presence of celecoxib not the expression of COX-2 compared with that in cells treated with EPA have suggested that PGE2 can stimulate cancer cell growth R. B. M. D. Prostaglandin E2 a for cancer growth and PubMed Scopus Google the effect of both PGE2 and PGE3 on human lung cancer cell proliferation was investigated. A549 cells were exposed to PGE2 or PGE3 for PGE2 μM) produced only a increase in cell PGE3 μM) inhibited the growth of cells by 37.1% (P < of PGE3 to the A549 cells to a reduction in cell proliferation compared with that in the cells treated with PGE2 (P < 0.05). The effect of PGE3 on A549 cell proliferation was In contrast to that of A549 cells, exposure of cells to 1 μM PGE3 the synthesis of cells by only The role of PGE3 in cell was in A549 cells treated with EPA and a combination of EPA and selective COX A549 cells were exposed to EPA (25 AA (25 EPA and celecoxib and 10 and EPA and and μM) for h. and were by the cells with and was with a When cells were exposed to EPA (25 μM) for the of cells were and to be as by with the cells were exposed to the combination of EPA and celecoxib cell was as by the increased of cells by compared with with EPA alone. In only cell and were using a Exposure of cells to μM EPA to a reduction in cell (P < and increased cells by < compared with control cells. In exposure of cells to a of AA not the growth of A549 cells. Furthermore, cells were exposed to EPA and celecoxib and 10 the number of cells was by and respectively, compared with with EPA alone. The effect of celecoxib on cell growth inhibition was a selective not the inhibitory effect of EPA on A549 cell growth data that the inhibitory effect of EPA on the growth of A549 cells be associated with the formation of on A549 cells. were cultured in with were in μM and treated with EPA or AA (25 and celecoxib in and was and was on a as in and EPA to in the cells. When cells were exposed to EPA and cell by EPA was reversed by as by a 50% reduction in cells compared with EPA alone. are of with from < from a < and < have suggested that production of prostaglandins be associated with the effects of the consumption of ω-3 fatty acids H. P. fatty acids and in human and PubMed Scopus Google Scholar). In contrast to data from studies with PGE2, little is of the pharmacology of and to PGE3. of PGE3 in biological as as within cell has been and has studies of the formation of unique prostaglandin and effects on the formation of PGE2 within normal and cell a selective and for the of PGE3, showed that PGE3 is formed within 5 of exposure of A549 cells to EPA P. T. Fischer R.A. of and 3-series prostaglandins in cultured tumor PubMed Scopus Google Scholar). In the have for the first that both human lung cancer cells and cloned ovine and COX-2 and human recombinant COX-2 enzymes are of PGE3 from EPA in a and In addition, that PGE3 inhibited the proliferation of A549 human lung cancer cells but not the growth of normal cells. Furthermore, of PGE3 to cells resulted in the inhibition of cell proliferation in A549 cells. data that celecoxib can cell in is associated with a formation of PGE3 in A549 cells. expression of COX-2 and the production of PGE2 have been in the of of and lung Cyclooxygenase and Biophys. Acta. 2000; Google Scholar). In A549 human lung cancer cells to the formation of PGE2 as as the formation of PGE3 from Exposure of A549 cells to EPA to an increase in PGE3 levels that 2 after the of is that rapid of 3-series prostaglandin which to the level of PGE3 in the Both the and extracellular levels of PGE3, however, were h. for is that PGE3 be To PGE2 and PGE3 were with only or cells The levels of both prostaglandins after of not that of the prostaglandins had PGE3 be by prostaglandin K.E. M. Fischer Eicosapentaenoic and arachidonic of metabolism and activity in murine 24: PubMed Scopus (22) Google Scholar). or levels of PGE3 in A549 cells were in cells that had not been exposed to The for in the that the to a of We of for in and levels of EPA in from not the levels of EPA in the not the of the reported activity in cells in be of EPA in In of the ability of COX to form 3-series prostaglandins, from were that have a high of as to COX-2 J.A. S. and biochemical of 1979; PubMed Scopus Google Scholar). To the production of the the formation of both PGE2 and PGE3 from cloned and COX-2 The production of PGE2 by ovine and human recombinant COX-2 exposed to AA was to that reported N. M. Fatty acid substrate of human and Full Text Full Text PDF PubMed Scopus Google Scholar, Differential inhibition of prostaglandin by and Full Text PDF PubMed Google Scholar). In the formation of PGE3 with human recombinant COX-2 was to 18-fold higher than that from These data are with reported by N. M. Fatty acid substrate of human and Full Text Full Text PDF PubMed Scopus Google Scholar) that the of of EPA are greater with cell and of COX-2 than are with of COX-1. In contrast to from studies that EPA with is a substrate for and as by the of J.A. S. and biochemical of 1979; PubMed Scopus Google Scholar), data that the COX-2-mediated formation of PGE3 from EPA was only less than the formation of PGE2 from AA using human recombinant data that EPA is a substrate for human COX-2 than is for was shown that EPA and AA the expression of COX-2 and in Y. Fischer Prostaglandin E2 of cyclooxygenase expression in is prostaglandin Lipid Res. 2000; Full Text Full Text PDF PubMed Google Scholar) and K.C. M. R. S. Fish oil cyclooxygenase (COX-2) expression by Res. 1999; Full Text PDF PubMed Scopus Google Scholar). We that DHA, and AA μM) are of the expression of COX-2 in A549 cells in h. In contrast to a study that the of COX-2 expression in cells within of Y. Fischer Prostaglandin E2 of cyclooxygenase expression in is prostaglandin Lipid Res. 2000; Full Text Full Text PDF PubMed Google Scholar), not a of COX-2 expression by EPA in A549 cells of This that the rapid increase of PGE3 in A549 cells result from the metabolism of EPA by both and COX-2 enzymes in the cells. the levels of COX-2 were increased by exposure of A549 cells to the formation of PGE2 by AA in cells was actually by exposure to The of the of COX-2 expression in the presence of COX-2 however, is example, a number of in vivo studies have shown that ingestion of fish oil both EPA and inhibited or breast tumor growth and that anticancer effect have been associated with the inhibition of expression of COX-2 the tumor Omega-3 fatty acids to cancer Google Scholar, C.V. Hirose Y. Reddy of by and of dietary fatty Res. 2001; Google Scholar). In the of AA not the formation of PGE3 by EPA in A549 cells. even the expression of COX-2 increase within cells, the effects of EPA both a decrease in the COX-2-mediated formation of PGE2 and the formation of PGE3, with effects on inhibition of tumor cell in study was the ability of PGE3 to inhibit the proliferation of A549 human lung cancer cells. When A549 tumor lung cells were exposed to both prostaglandins, PGE2 not the inhibitory effect of PGE3 on the proliferation of cells. celecoxib 5 a to a 50% reduction in PGE2 formation in A549 cells P. T. R.A. of arachidonic acid in cultured tumor cells using 2001; PubMed Scopus Google Scholar), reversed cell as by This with the reduction of PGE3 formation in cells treated with EPA and These results indicate that the inhibitory effect of EPA on tumor cell proliferation is in to the formation of PGE3, which as a of cell proliferation. mechanisms have been to the cell growth inhibitory effect of have for example, that dietary EPA and DHA can in that in their inhibitory effect on cell proliferation as as the of in tumor cells (2Bartsch H. Nair J. Owen R.W. Dietary polyunsaturated fatty acids and cancers of the breast and colorectum: emerging evidence for their role as risk modifiers.Carcinogenesis. 1999; 20: 2209-2218Crossref PubMed Scopus (402) Google Scholar, R. Dietary n-3 and PubMed Scopus Google Scholar). To is the first study to that PGE3 effects on human cell lung cancer cells. In contrast to not a effect of PGE2 on the growth of cancer or normal cells (12McKenzie K.E. Bandyopadhyay G.K. Imagawa W. Sun K. Nandi S. ω-3 and ω-6 fatty acids and PGE2 stimulate the growth of normal but not tumor mouse mammary epithelial cells: evidence for alterations in the signaling pathways in tumor cells.Prostaglandins Leukot. Essent. Fatty Acids. 1994; 51: 437-443Abstract Full Text PDF PubMed Scopus (13) Google Scholar, R. B. M. D. Prostaglandin E2 a for cancer growth and PubMed Scopus Google Scholar). A for is that the level of PGE2 within A549 cells is high the of PGE2 have been of the growth of tumor cells. is that the effect of PGE2 on cell proliferation be cell example, PGE2 can the of normal mammary epithelial cell or cancer cell growth of prostaglandin biosynthesis by eicosapentaenoic 1979; Full Text PDF PubMed Scopus Google Scholar, H. J. R.N. Prostaglandin E2 growth and of cells.J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), have an effect on cells or T. S. H. K. Y. H. H. Y. R. Y. of prostaglandin and pathways growth inhibition in human cell PubMed Google Scholar). the and of the inhibitory effect of PGE3 on the proliferation of tumor cells is of and In have that A549 human lung cancer cells can and export PGE3 using EPA as a substrate in a and ovine and COX-2 and human recombinant COX-2 were to PGE3 with However, the ability of COX-2 to form PGE3 was much greater than that of COX-1. PGE3, unlike PGE2, inhibited the proliferation of human lung cancer cells and the effect of PGE2 on cell proliferation in A549 human lung cancer cells. to the formation of PGE3 in both cells and the increased expression of COX-2 in cancer cells and the increased production of PGE3 from EPA a for the anticancer activity of fish oil that This was in by and and of arachidonic acid of cyclooxygenase docosahexaenoic acid eicosapentaenoic acid normal human bronchial epithelial prostaglandin E3