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.
Highlights
Endometrial cancer is the most common gynecologic malignancy and a major cause of morbidity and mortality in women worldwide, with nearly 200,000 cases diagnosed every year and a rising incidence in postmenopausal women [1,2,3,4]
To investigate the potential protective role of n-3 polyunsaturated fatty acids (PUFA) against endometrial cancer, we first examined the effect of docosahexenoic acid (DHA) on the proliferation of cultured endometrial carcinoma HEC-1-A, HEC-1-B, and RL95-2 cell lines
These results demonstrate that DHA effectively inhibits endometrial cancer cell growth in vitro
Summary
Endometrial cancer is the most common gynecologic malignancy and a major cause of morbidity and mortality in women worldwide, with nearly 200,000 cases diagnosed every year and a rising incidence in postmenopausal women [1,2,3,4]. The precise cause of endometrial cancer is unknown, various associated risk factors for the disease have been identified. The main risk factors for the development of endometrial carcinoma are obesity and chronic unopposed estrogen stimulation of the endometrium [5,6,7]. Authors' Affiliations: 1Department of Oncology, Nanfang Hospital; 2Department of Cell Biology, School of Basic Medical Sciences; 3Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou; and 4State Key Laboratory of Reproductive Medicine and Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China. Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/).
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