title: Inhibition of endometrial cancer by n-3 polyunsaturated fatty acids in preclinical models.
abstract: Although preclinical and epidemiologic studies have shown the importance of n-3 polyunsaturated fatty acids (PUFA) in the prevention of hormone-responsive cancers such as breast cancer, evidence of the association between n-3 PUFAs and endometrial cancer risk is limited and no previous study has examined the effect of n-3 PUFAs on endometrial cancer in cellular and animal models. In this study, we demonstrated that docosahexenoic acid (DHA) dose- and time-dependently inhibited endometrial cancer cell proliferation, colony formation, and migration and promoted apoptosis. Dietary n-3 PUFAs efficiently prevented endometrial cancer cell growth in xenograft models. Moreover, ectopic expression of fat-1, a desaturase, catalyzed the conversion of n-6 to n-3 PUFAs and produced n-3 PUFAs endogenously, also suppressed endometrial tumor cell growth and migration, and potentiated apoptosis in endometrial cancer cell lines. Interestingly, implanted endometrial cancer cells were unable to grow in fat-1 transgenic SCID mice. Further study revealed that mTOR signaling, which plays an essential role in cell proliferation and endometrial tumorigenesis, is a target of n-3 PUFAs. Exogenous or endogenous n-3 PUFAs efficiently suppressed both mTOR complex 1 (mTORC1) and mTORC2 in vitro and in vivo. Moreover, both dietary n-3 PUFAs and transgenic expression of fat-1 in mice effectively repressed mTORC1/2 signaling and endometrial growth elicited by unopposed estrogen. Taken together, our findings provide comprehensive preclinical evidences that n-3 PUFAs efficiently prevent endometrial cancer and establish mTORC1/2 as a target of n-3 PUFAs.
authors.affiliation: Department of Oncology, Nanfang Hospital;
authors.forename: Hang
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Oncology, Nanfang Hospital;
authors.forename: Hongjun
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Oncology, Nanfang Hospital;
authors.forename: Miao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Oncology, Nanfang Hospital;
authors.forename: Minhong
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences;
authors.forename: Pinglin
authors.initials: P
authors.lastname: Lai
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences;
authors.forename: Heling
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences;
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences;
authors.forename: Chunhong
authors.initials: C
authors.lastname: Jia
authors.affiliation: Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou; and.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Reproductive Medicine and Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences; wlilyu@hotmail.com baixc15@smu.edu.cn.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou; and wlilyu@hotmail.com baixc15@smu.edu.cn.
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002384:Catalysis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004032:Diet; D016889:Endometrial Neoplasms / Q000188:drug therapy*; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D046912:Multiprotein Complexes / Q000378:metabolism; D009368:Neoplasm Transplantation; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013629:Tamoxifen / Q000737:chemistry; D014945:Wound Healing
chemical_list: D015525:Fatty Acids, Omega-3; D046912:Multiprotein Complexes; D013629:Tamoxifen; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases