G-protein-coupled receptors mediate ω-3 PUFAs-inhibited colorectal cancer by activating the Hippo pathway.
G-protein-coupled receptors mediate ω-3 PUFAs-inhibited colorectal cancer by activating the Hippo pathway.
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DOI：
10.18632/oncotarget.11089
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发表时间：
2016-09-06
期刊：
影响因子：
--
通讯作者：
Hong W
中科院分区：
文献类型：
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作者：
Zhang K;Hu Z;Qi H;Shi Z;Chang Y;Yao Q;Cui H;Zheng L;Han Y;Han X;Zhang Z;Chen T;Hong W
结直肠癌(CRC)是导致高死亡率的常见癌症之一。然而，由于副作用的存在，长期应用抗肿瘤治疗对结直肠癌是不可行的。Omega-3多不饱和脂肪酸(ω-3 PUFA)，特别是DHA和EPA，对结直肠癌具有保护作用，但其机制尚不清楚。在此，我们发现ω-3多不饱和脂肪酸在体外抑制结直肠癌细胞的增殖和诱导细胞凋亡，并在体内减轻AOM/DSS诱导的小鼠结直肠癌。此外，ω-3PUFAs促进YAP的磷酸化和胞质滞留，这一作用是由MST1/2和LATS1介导的，提示典型的河马途径参与了ω-3PUFAs的作用。我们进一步证实，ω-3多不饱和脂肪酸增加PYAP是由GPR40和GPR120介导的，GPR40和GPR120随后通过GαS激活PKA，从而诱导河马通路的激活。这些结果提供了一个新的信号转导途径：DHA/EPA-GPR40/120-GαS-PKA-MST1/2-LATS1-YAP，该信号通路与ω-3PUFAs诱导的抑制细胞增殖和促进细胞凋亡有关，提示了ω-3PUFAs抗癌作用的机制。
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 (ω-3 PUFAs), particularly DHA and EPA, exert protection against CRC, but the mechanisms are unclear. Here, we show that ω-3 PUFAs inhibit proliferation and induce apoptosis of CRC cells in vitro and alleviate AOM/DSS-induced mice colorectal cancer in vivo. Moreover, ω-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 ω-3 PUFAs function. We further confirmed that increase of pYAP by ω-3 PUFAs was mediated by GPRs, including GPR40 and GPR120, which subsequently activate PKA via Gαs, thus inducing the Hippo pathway activation. These data provide a novel DHA/EPA-GPR40/120-Gαs-PKA-MST1/2-LATS1-YAP signaling pathway which is linked to ω-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 ω-3 PUFAs.