title: Elevation of ω-3 Polyunsaturated Fatty Acids Attenuates PTEN-deficiency Induced Endometrial Cancer Development through Regulation of COX-2 and PGE2 Production.
abstract: Endometrial cancer is one of the most common gynecologic malignancies. Phosphatase and tensin homologue (PTEN)-mutation is frequently identified in endometrial cancer patients. Although high dietary intake of ω-3 polyunsaturated fatty acids (PUFAs) has been associated with reduced risk of endometrial cancer, the underlying mechanisms is still unknown. To this end, we evaluated the impact of ω-3 PUFAs using several endometrial cancer cellular and animal models. While ~27% and 40% of heterozygotic PTEN mutant mice developed endometrial cancer and atypical complex hyperplasia, respectively, none of the PTEN(+/-) mice developed cancer when we overexpressed an mfat-1 transgene, which allowed endogenous production of ω-3 PUFAs. Fish oil-enriched diet or expression of mfat-1 transgene significantly inhibited the growth of xenograft tumor derived from RL95-2 cells bearing a PTEN null mutation. At cellular level, ω-3 PUFAs treatment decreased the viability of RL95-2 cells, AKT phosphorylation, and cyclin D1 expression. These molecular events are primarily mediated through reduction of cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production. Exogenous PGE2 treatment completely blunted the impact of ω-3 PUFAs on endometrial cancer. Thus, we revealed the direct inhibitory effects of ω-3 PUFAs on endometrial cancer development and the underlying mechanisms involving reduction of COX-2 and PGE2.
authors.affiliation: The Center of Metabolic Disease Research, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
authors.forename: Jinshun
authors.initials: J
authors.lastname: Pan
authors.affiliation: The Center of Metabolic Disease Research, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
authors.forename: Lixian
authors.initials: L
authors.lastname: Cheng
authors.affiliation: The Center of Metabolic Disease Research, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
authors.forename: Xinyun
authors.initials: X
authors.lastname: Bi
authors.affiliation: The Center of Metabolic Disease Research, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The Center of Metabolic Disease Research, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Bai
authors.affiliation: The Center of Metabolic Disease Research, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
authors.forename: Fanghong
authors.initials: F
authors.lastname: Li
authors.affiliation: The Center of Metabolic Disease Research, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
authors.forename: Allan Z
authors.initials: AZ
authors.lastname: Zhao
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis*; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015525:Fatty Acids, Omega-3 / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D055432:Metabolomics / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D015820:Cadherins; D015777:Eicosanoids; D015525:Fatty Acids, Omega-3; C502406:fat1 protein, mouse; D019938:Cyclin D1; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; D015232:Dinoprostone