Inhibition of Endometrial Cancer by n-3 Polyunsaturated Fatty Acids in Preclinical Models

• Published in: Cancer prevention research (Philadelphia, Pa.) Vol. 7; no. 8; pp. 824 - 834
• Main Authors: Zheng, Hang, Tang, Hongjun, Liu, Miao, He, Minhong, Lai, Pinglin, Dong, Heling, Lin, Jun, Jia, Chunhong, Zhong, Mei, Dai, Yifan, Bai, Xiaochun, Wang, Liping
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-08-2014
• Subjects: Animals; Apoptosis; Biological and medical sciences; Catalysis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Diet; Endometrial Neoplasms - drug therapy; Fatty Acids, Omega-3 - administration & dosage; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Medical sciences; Mice; Mice, Inbred BALB C; Mice, SCID; Miscellaneous; Multiprotein Complexes - metabolism; Neoplasm Transplantation; Prevention and actions; Public health. Hygiene; Public health. Hygiene-occupational medicine; Tamoxifen - chemistry; TOR Serine-Threonine Kinases - metabolism; Tumors; Wound Healing; Endometrium cancer; Uterine diseases; Polyunsaturated fatty acid; Unsaturated fatty acid; Lipids; Inhibitor; Models; Malignant tumor; Inhibition; n-3 fatty acid; Cancer; Female genital diseases
• ISSN: 1940-6207; 1940-6215
• DOI: 10.1158/1940-6207.CAPR-13-0378-T

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.