Inhibition of endometrial cancer by n-3 polyunsaturated fatty acids (PUFAs) in preclinical models
Menée in vitro et à l'aide de xénogreffes sur des modèles murins, cette étude montre que des acides gras polyinsaturés n-3 peuvent inhiber la carcinogenèse de l'endomètre
Although preclinical and epidemiological studies have shown the importance of n-3 polyunsaturated fatty acids (PUFAs) 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 (severe combined immune deficiency) mice. Further study revealed that mammalian target of rapamycin (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 oestrogen. 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.