G-protein-coupled receptors mediate ω-3 PUFAs-inhibited colorectal cancer by activating the Hippo pathway

被引:42
作者
Zhang, Kun [1 ]
Hu, Zhimei [1 ]
Qi, Haixia [1 ]
Shi, Zhemin [1 ]
Chang, Yanan [1 ]
Yao, Qingbin [1 ]
Cui, Hongmei [1 ]
Zheng, Lina [1 ]
Han, Yawei [1 ]
Han, Xiaohui [1 ]
Zhang, Zhen [1 ]
Chen, Ting [1 ]
Hong, Wei [1 ]
机构
[1] Tianjin Med Univ, Sch Basic Med Sci, Dept Histol & Embryol, Tianjin 300070, Peoples R China
基金
中国国家自然科学基金;
关键词
omega-3; PUFAs; Hippo pathway; GPR; colorectal cancer; YAP; YES-ASSOCIATED PROTEIN; TRANSGENIC MICE RICH; YAP PATHWAY; FATTY-ACIDS; CELL-PROLIFERATION; SIZE-CONTROL; EXPRESSION; CATENIN; TUMORIGENESIS; GROWTH;
D O I
10.18632/oncotarget.11089
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Colorectal cancer (CRC) is one of the most common cancers leading to high mortality. However, long-term administration of anti-tumor therapy for CRC is not feasible due to the side effects. Omega-3 polyunsaturated fatty acids (omega-3 PUFAs), particularly DHA and EPA, exert protection against CRC, but the mechanisms are unclear. Here, we show that omega-3 PUFAs inhibit proliferation and induce apoptosis of CRC cells in vitro and alleviate AOM/DSS-induced mice colorectal cancer in vivo. Moreover, omega-3 PUFAs promote phosphorylation and cytoplasmic retention of YAP and this effect was mediated by MST1/2 and LATS1, suggesting that the canonical Hippo Pathway is involved in omega-3 PUFAs function. We further confirmed that increase of pYAP by omega-3 PUFAs was mediated by GPRs, including GPR40 and GPR120, which subsequently activate PKA via Gas, thus inducing the Hippo pathway activation. These data provide a novel DHA/EPA-GPR40/120-G beta s-PKA-MST1/2-LATS1-YAP signaling pathway which is linked to omega-3 PUFAs-induced inhibition of cell proliferation and promotion of apoptosis in CRC cells, indicating a mechanism that could explain the anti-cancer action of omega-3 PUFAs.
引用
收藏
页码:58315 / 58330
页数:16
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