?-3 Polyunsaturated Fatty Acids Attenuates Endometrial Cancer Development And Progression And The Related Mechanisms

Background:Endometrial cancer is a very common gynecologic malignancy and the fourth most common cancer for women worldwide.There are nearly 200,000 cases diagnosed each year,comprising 6%of female cancers.Epidemiological studies have revealed a protective effect of ?-3 PUFAs against,and a seemingly promoting effect of co-6 PUFAs for,the development of cancers.High dietary intake of ?-3 PUFAs in food and supplements were associated with reduced risk of endometrial cancer.However,the direct impact as well as the underlying mechanisms of ?-3 PUFAs-mediated growth inhibition is still unknown.Objective:To investigate the impact and the underlying mechanisms of ?-3 PUFA on primary endometrial cancer development.Methods:1.A primary endometrial cancer model,which developed from mice bearing heterozygotic PTEN null mutation,was used to investigate the effects of ?-3 PUFAs on tumorgenesis.2.Endometrial tumor xenograft models were used to investigate the effects of mfat-1 expressio on endometrial cancer growth.3.Endometrial tumor xenograft models were used to investigate the effects of co-3 PUFA-enriched diet on endometrial cancer growth.4.Metabolomic analysis of eicosanoids was performed in RL95-2 endometrial cancer after AA or DHA treatment.5.Signaling pathways involved in ?-3 PUFAs-mediated growth inhibition of endometrial cancer were investingResults:1.?-3 PUFAs attenuates primary endometrial cancer development and inhibit endometrial cancer cell growth in xenograft models.In primary endometrial cancer models,75%of endometrial hyperplasia and 25%of cancer were found in PTEN+/-mice.While only 50%of endometrial hyperplasia were found in mfat-1;PTEN+/-mice,we failed to observe tumor growth in this group.A diet containing 5%fish-oil or expression of mfat-1 transgene strongly inhibited tumor growth in a xenograft model with RL95-2 cells carrying PTEN null mutations.2.?-3 PUFAs inhibit endometrial cancer cell growth in vitro.Analysis of fatty acid compositions confirmed the function of mfat-1 protein in RL95-2 cells.The data showed a decrease in ?-6 PUFAs level and an increase in ?-3 PUFAs levels,leading to a significantly decreased ratio of co-6/?-3 PUFAs.Exogenous DHA inhibited cells viability in RL95-2 cells in vitro.However,EPA has little effect on viability of RL95-2 cells.The mfat-1 expression significantly suppressed cell viability as compared to the controls.3.The mechanisms underlying ?-3 PUFAs-mediated inhibition of endometrial lesion.?-3 PUFAs treatment significantly inhibited Akt phosphorylation and cyclin D1 expression in endometrial cancer cells.Metabolomic analysis of eicosanoids showed that the levels of 29 AA-derived metabolites were increased in RL95-2 cells treated with AA,such as PGE2,LTB4,5-HETE,12-HETE,15-HETE,20-HETE,11,12-EET,and 14,15-EET.RL95-2 cells expressing mfat-1 gene decreased the levels of these 8 eicosanoids.DHA treatment only decreased PGE2 production.Metabolomic analysis of products showed elevated levels of 13 DHA-derived eicosanoids in RL95-2 cells following the treatment with exogenous DHA.Expression of mfat-1 transgene promoted 13-HDoHE and 19,20-EDP production.IHC and western blotting assays showed that exogenous DHA treatment and mfat-1 expression decreased COX-2 expression significantly.Exogenous PGE2 treatment partially countered mfat-1-induced cell cycle arrest,Akt phosphorylation,and cyclin D1 expression.Conclusion:?-3 PUFAs suppress cell proliferation and tumorgenesis in endometrial cancer,through reduction of COX-2 expression and PGE2 production,as well as a decrease of Akt phosphorylation and cyclin D1 expression.