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

// Kun Zhang 1, * , Zhimei Hu 1, * , Haixia Qi 1 , Zhemin Shi 1 , Yanan Chang 1 , Qingbin Yao 1 , Hongmei Cui 1 , Lina Zheng 1 , Yawei Han 1 , Xiaohui Han 1 , Zhen Zhang 1 , Ting Chen 1 , Wei Hong 1 1 Department 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: hongwei@tmu.edu.cn Keywords: omega-3 PUFAs, Hippo pathway, GPR, colorectal cancer, YAP Received: April 16, 2016 Accepted: July 10, 2016 Published: August 5, 2016 ABSTRACT 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.