title: G-protein-coupled receptors mediate ω-3 PUFAs-inhibited colorectal cancer by activating the Hippo pathway.
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.
authors: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors: Kun
authors: K
authors: Zhang
authors: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors: Zhimei
authors: Z
authors: Hu
authors: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors: Haixia
authors: H
authors: Qi
authors: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors: Zhemin
authors: Z
authors: Shi
authors: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors: Yanan
authors: Y
authors: Chang
authors: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors: Qingbin
authors: Q
authors: Yao
authors: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors: Hongmei
authors: H
authors: Cui
authors: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors: Lina
authors: L
authors: Zheng
authors: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors: Yawei
authors: Y
authors: Han
authors: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors: Xiaohui
authors: X
authors: Han
authors: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors: Zhen
authors: Z
authors: Zhang
authors: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors: Ting
authors: T
authors: Chen
authors: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors: Wei
authors: W
authors: Hong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001397:Azoxymethane / Q000737:chemistry; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000628:therapy; D003593:Cytoplasm / Q000378:metabolism; D016264:Dextran Sulfate / Q000737:chemistry; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D019073:HT29 Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D015525:Fatty Acids, Omega-3; D010750:Phosphoproteins; D043562:Receptors, G-Protein-Coupled; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D016264:Dextran Sulfate; D017346:Protein Serine-Threonine Kinases; D001397:Azoxymethane
keywords: GPR; Hippo pathway; YAP; colorectal cancer; omega-3 PUFAs