mTORC1/2 targeted by n-3 polyunsaturated fatty acids in the prevention of mammary tumorigenesis and tumor progression
mTORC1/2 targeted by n-3 polyunsaturated fatty acids in the prevention of mammary tumorigenesis and tumor progression
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n-3 多不饱和脂肪酸靶向 mTORC1/2 预防乳腺肿瘤发生和肿瘤进展
DOI：
10.1038/onc.2013.402
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发表时间：
2014-09-11
期刊：
影响因子：
8
通讯作者：
Bai, X.
中科院分区：
文献类型：
--
作者：
Chen, Z.;Zhang, Y.;Bai, X.
尽管流行病学和临床前研究已经显示了n-3多不饱和脂肪酸（PUFA）对乳腺癌的预防作用，但数据中仍然存在不一致性，其潜在机制仍不清楚。在这项研究中，我们确定了哺乳动物雷帕霉素（mTOR）信号，这在细胞增殖和乳腺肿瘤发生中起着至关重要的作用，作为目标的n-3 PUFA。在乳腺癌细胞系中，n-3 PUFA快速有效地抑制mTOR复合物1（mTORC 1）和mTORC 2及其下游信号传导，随后抑制细胞增殖和血管生成，同时促进细胞凋亡。进一步的研究表明，mTOR-raptor复合物的n-3多不饱和脂肪酸的稳定性可能有助于他们对mTORC 1的抑制作用。重要的是，利用四种互补且良好对照的动物模型来鉴定n-3 PUFA在预防乳腺癌发生和进展中的作用和分子靶点，即：（1）具有高膳食摄入n-3 PUFA的化学诱导的乳腺肿瘤大鼠;（2）植入稳定表达fat-1的乳腺肿瘤细胞系的裸鼠，fat-1是一种催化n-6转化为n-3 PUFA并内源性产生n-3 PUFA的去饱和酶;（3）植入乳腺肿瘤细胞的fat-1转基因严重联合免疫缺陷小鼠;（4）侵袭性乳腺癌模型fat-1转基因小鼠乳腺肿瘤病毒-多瘤病毒中T癌基因双杂交小鼠。总之，膳食和内源性n-3 PUFA在体外和体内消除mTORC 1/2途径的活性，并防止乳腺癌发生、肿瘤生长和转移。综上所述，我们的研究结果令人信服地阐明了n-3 PUFAs和乳腺癌预防之间的因果关系，并将mTORC 1/2确定为n-3 PUFAs的靶点。
Although epidemiological and preclinical studies have shown the preventative effects of n-3 polyunsaturated fatty acids (PUFAs) on breast cancer, inconsistencies still remain in the data and the underlying mechanisms remain unclear. In this study, we identified mammalian target of rapamycin (mTOR) signaling, which plays an essential role in cell proliferation and breast tumorigenesis, as a target of n-3 PUFAs. In breast cancer cell lines, n-3 PUFAs rapidly and efficiently suppress both mTOR complex 1 (mTORC1) and mTORC2 and their downstream signaling, and subsequently inhibit cell proliferation and angiogenesis while promoting apoptosis. Further study indicates that stabilization of the mTOR-raptor complex by n-3 PUFAs may contribute to their inhibitory effect on mTORC1. Importantly, four complementary and well-controlled animal models were utilized to identify the role and molecular target of n-3 PUFAs in the prevention of breast carcinogenesis and progression, namely:(1) chemically induced mammary tumor rats with a high dietary intake of n-3 PUFAs;(2) nude mice implanted with mammary tumor cell lines stably expressing fat-1, a desaturase that catalyzes the conversion of n-6 to n-3 PUFAs and produces n-3 PUFAs endogenously;(3) fat-1 transgenic severe combined immune deficiency mice implanted with breast tumor cells; and (4) the fat-1 transgenic mouse mammary tumor virus-polyoma virus middle T oncogene double-hybrid mice, a model of aggressive breast cancer. In summary, dietary and endogenous n-3 PUFAs abrogate the activity of mTORC1/2 pathways in vitro and in vivo and prevent breast carcinogenesis, tumor growth and metastasis. Taken together, our findings convincingly clarify the causal relationship between n-3 PUFAs and breast cancer prevention and establish mTORC1/2 as a target of n-3 PUFAs.