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  • br Introduction Prostate cancer is the most commonly diagnos


    Introduction Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths in men in the United States, accounting for about 30,000 cancer deaths annually [1]. Epidemiological studies that show geographical variations in prostate cancer incidence and mortality have provided evidence that environmental and lifestyle-related factors, including diet, associate with the occurrence of prostate cancer [2]. Of particular interest are the n-3 PUFAs rich in fish oil, such as docosahexaenoic LDN-212854 (DHA) and eicosapentaenic acid (EPA), which are converted by fish from alpha linolenic acid (αLNA; 18:3 n-3) of ingested cold-water vegetation [3]. Even though there are abundant experimental evidences that the DHA enrich in fish oil prevent carcinogenesis. However, the mechanisms underlying the beneficial effects of DHA on prostate cancer are still poorly understood, in part because molecular signaling pathways of DHA are only beginning to be revealed. 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 epinephrine 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.