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  • The Hippo pathway has been well established as a tumor


    The Hippo pathway has been well established as a tumor suppressor pathway and is involved in many diverse biologic processes including cell growth, cell death, and organ size control in organisms, ranging from Drosophila to mammals [4]. Central to this pathway is a kinase cascade in which the Ste20-like kinases MST1 and MST2, in complex with a regulatory protein salvador (Sav1), phosphorylate and activate the NDR family kinases, LATS1 and LATS2, which also form a complex with a regulatory protein Mob1 [5]. LATS1 and LATS2 inhibit YAP by direct phosphorylation at S127, which results in YAP binding to 14-3-3 and cytoplasmic translocation [6]. Phosphorylation of YAP at S381 by LATS1 and LATS2 kinases can also promote its ubiquitination-dependent degradation [7]. YAP acts mainly through TEAD family transcription factors to stimulate expression of genes that promote proliferation and inhibit apoptosis [8]. Moreover, abnormal activation of YAP has been associated with human cancers including prostate cancer [6,9], suggesting an important role for the Hippo pathway in tumorigenesis. Recent studies revealed that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) signaling [[10], [11], [12]]. Activation of Gαs-coupled receptors by Adenine sulfate sale or glucagons stimulation increases LATS1/2 kinase activity, thus resulting in inhibition of YAP function [11]. Remarkably, FFAR4 (GPR120) was recently proposed to functions as n-3 PUFAs receptor in macrophages and mediates anti-inflammatory effects [13]. Long-chain PUFAs can also activate FFAR1 (GPR40) [14]. This allows us to speculate that DHA protects against prostate cancer development by regulating the Hippo pathway through FFAR1 and FFAR4.
    Materials and methods
    Discussion Still today, studies continue to demonstrate the anticancer effect of n-3 PUFAs; however, the mechanisms of action of n-3 PUFAs are still not fully understood. Several molecular mechanisms whereby n-3 PUFAs may modify the carcinogenic process have been proposed such as suppression of arachidonic acid-derived eicosanoid metabolism [19], influences on the production of free radicals and cellular oxidative metabolism [20]and regulation of intracellular signalling pathways [21]. GPCR represents the largest family of plasma membrane receptors that can be activated or inactivated by a wide range of physiological ligands or pharmaceutical drugs. It has been reported that TAK-875, a FFAR1 agonist, had a profound and selective inhibitory effect on the growth of the human melanoma cell lines, suggesting FFAR1 may provide a link between DHA and cancer [22]. In addition, FFAR4 was recently proposed to serve as a specific sensor for n-3PUFAs in macrophages that may mediate the putative insulin-sensitizing and anti-diabetic effects of n-3 PUFAs in vivo by repressing macrophage -induced tissue inflammation [13]. All these studies suggest that DHA may inhibit prostate cancer cell lines proliferation dependent on GPCRs. As the results shown in the Fig. 3E and F, knockdown FFAR1 and FFAR4 abolished the effect of DHA on the PC3 cells. Moreover, we also found that down regulation of FFAR1 and FFAR4 inhibit PC3 cells proliferation (Fig. 4C), consistent with previous study that FFAR4 functions as a tumor-promoting receptor in human colorectal carcinoma [23]. However, whether FFAR1 and FFAR4 are over-expressed in prostate cancer required further study. Our results indicate that DHA specifically induces cell growth inhibition and apoptosis in cultured human prostate cancer cells through GPCRs. Hippo signaling is an emerging tumor suppressor pathway that plays key roles in normal physiology and tumorigenesis through the regulation of cellular proliferation and survival [4]. In humans, YAP is over-expressed as a result of genomic amplification of the 11q22 locus in a wide spectrum of human cancer cell lines and primary tumors [8,9]. In addition, several lines of evidence suggest that extracellular ligands modulate the Hippo pathway through GPCR signaling [11]. So it is very important to explore whether DHA induced cell growth inhibition and apoptosis of human prostate cancer cells via YAP. As the results shown in Fig. 2, DHA induced YAP phosphorylation in androgen-independent prostate cancer cell lines PC3 and DU145 but not in androgen-dependent prostate cancer cell line LNCaP. To verify this, we further investigate whether DHA promotes LATS phosphorylation in PC3 and LNCaP. Not surprisingly, DHA phosphorylates and activates LATS in PC3 but not LNCaP, suggesting DHA inhibits LNCaP proliferation in a different way. Our previous study has shown that DHA inhibits the growth of hormone-dependent prostate cancer cells LNCaP via promoting the degradation of the androgen receptor. The reason for this discrepancy may be that the mechanism of DHA induces cell growth inhibition and apoptosis are various in cell lines of different species and backgrounds. Moreover, it is known that LATS1/2 inactivates YAP by phosphorylating its Ser127 and Ser381 residues, Ser127 phosphorylation mediates interaction with 14-3-3 proteins, which sequester YAP in the cytoplasm [5]. On the other hand, Ser381 phosphorylation triggers successive phosphorylation on Ser384 by casein kinase-1 followed by SCFβ−TRCP E3 ubiquitin ligase-mediated degradation [7]. Our data has shown that the protein levels of YAP and TAZ were unaffected by DHA stimulation, suggesting that DHA potently inactivate YAP by phosphorylating its Ser127 residue, thus inducing YAP transfer to cytoplasm.