Research Papers:

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

Kun Zhang, Zhimei Hu, Haixia Qi, Zhemin Shi, Yanan Chang, Qingbin Yao, Hongmei Cui, Lina Zheng, Yawei Han, Xiaohui Han, Zhen Zhang, Ting Chen and Wei Hong _

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Oncotarget. 2016; 7:58315-58330. https://doi.org/10.18632/oncotarget.11089

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Kun Zhang1,*, Zhimei Hu1,*, Haixia Qi1, Zhemin Shi1, Yanan Chang1, Qingbin Yao1, Hongmei Cui1, Lina Zheng1, Yawei Han1, Xiaohui Han1, Zhen Zhang1, Ting Chen1, Wei Hong1

1Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China

*These authors have contributed equally to this work

Correspondence to:

Wei Hong, email: [email protected]

Keywords: omega-3 PUFAs, Hippo pathway, GPR, colorectal cancer, YAP

Received: April 16, 2016     Accepted: July 10, 2016     Published: August 5, 2016


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.

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