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.

Expression of long‑chain fatty acid receptor GPR40 is associated with cancer progression in colorectal cancer: A retrospective study

“…Our previous studies show that linoleic acid (an n-6 LCFA) and EA (a trans fatty acid), enhance colon carcinogenesis or metastability of CRC ( 5 , 6 , 9 , 10 ), whereas docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) (n-3 LCFAs) suppress colon carcinogenesis and enhance efficacy of chemotherapy regimens ( 27 ). The n-3 LCFAs also activate the hippo system via GPR40 and GPR120 to inhibit proliferation of CRC ( 28 ). Although blood TG level is widely utilized as a predictive clinical parameter, the identity of the fatty acids that constitute the TGs might be an important factor that determines the relationship between TGs and cancer risk.…”

Omega-3 polyunsaturated fatty acids as adjuvant therapy of colorectal cancer

“…O3FAs can exert anti-CRC activity following their interaction with surface free fatty acid (FFA) G protein-coupled receptors (GPCRs), thereby activating pro-apoptotic signalling [ 17 ]. These GPCRs have been shown to be expressed on non-epithelial cells such as adipocytes [ 38 , 39 ] and macrophages [ 40 ], on which activation can alter macrophage polarisation and reduce inflammation that is potentially important for anti-cancer activity of O3FAs.…”

“…In terms of COX-independent activity, both DHA and EPA have been shown to act as ligands for and inhibit cell proliferation via GPCRs such as GPR120 [ 44 ]. More recently, it has been reported that this interaction leads to the activation of the Hippo signalling pathway in LoVo and HT29 cells in vitro [ 17 ]. In vivo , GPCR activation resulted in a reduction in tumour burden in the azoxymethane (AOM)/dextran-sulphate model in Balb / c mice fed a 10% fish oil diet [ 17 ].…”

“…More recently, it has been reported that this interaction leads to the activation of the Hippo signalling pathway in LoVo and HT29 cells in vitro [ 17 ]. In vivo , GPCR activation resulted in a reduction in tumour burden in the azoxymethane (AOM)/dextran-sulphate model in Balb / c mice fed a 10% fish oil diet [ 17 ]. Another study reinforced the link between the anti-cancer effects of O3FAs and oxidative stress, showing that polyunsaturated fatty acids induced apoptosis in human CRC cells (LoVo and RKO cells) via the generation of reactive oxygen species and the induction of the caspase cascade [ 14 ].…”

Dual roles of yes-associated protein (YAP) in colorectal cancer

“…Recent studies have demonstrated that the Hippo/YAP pathway can crosstalk with other signalling pathways to regulate a series of biological functions in cancer, which is greatly depends on the important role of YAP that is not only mediated by the upstream signal molecule, but can also regulate a series of targets via interacting with transcription factors. By analysing studies published in recent years, we can summarize a complex regulatory network in which YAP is involved in a series of signalling pathways (Figure 1 ), such as those involving TGF-β/SMAD [ 67 , 68 ], Wnt/β-catenin [ 69 , 70 ], epidermal growth factor receptor (EGFR) [ 39 , 71 ], PI3K-AKT [ 72 , 73 ], NF-κB [ 69 , 74 ], Sonic Hedgehog (Shh) [ 75 , 76 ], mTOR [ 77 , 78 ], IL6 receptor (IL-6R) [ 79 , 80 ], GPCR [ 81 , 82 ], and Notch [ 83 , 84 ].…”