br Androgen interference with the action of arachidonic acid

Androgen interference with the action of arachidonic BPTES metabolites’ actions; the other side of the coin Arachidonic acid, being a polyunsaturated fatty acid present in the phospholipids of the membrane of cells, is highly abundant within the organism. It is mainly involved in cellular signaling and is a key intermediate of inflammation and vasodilation (Khan et al., 2014). In fact, when arachidonic acid is released from membrane phospholipids by phospholipase A2, its metabolism by various enzymes generates a number of biologically active intermediates, with important actions within the body, participating, among other, to inflammation and tumorigenesis (Yarla et al., 2016b, Yarla et al., 2016a). These metabolites are derived from the action of 4 enzyme groups: 1) cyclooxygenases that give rise to prostaglandins, prostacyclins and thromboxanes; 2) 15-lipoxygenase that generates 15-hydroperoxyeicosatetraenoic acid (15-HPETE) and subsequently lipoxins and eoxins; 3) 12-lipoxygenase that metabolizes arachidonic acid to 12-hydroperoxyeicosatetraenoic acid (12-HPETE) with hydroxyeicosatetraenoic acid (12-HETE) and hepoxilins as subsequent metabolites and 4) 5-lipoxygenase that generates 5-hydroperoxyeicosatetraenoic acid (5-HpETE) and subsequently leukotrienes, or 5-oxo-eicosatetraenoic acid (5-oxoETE) under the action of cytochrome P450 (CYP) enzymes such as CYP1A1, CYP1A2, CYP1B1, and CYP2S1 (Powell and Rokach, 2015), which are the main cellular detoxifying CYP isoforms. Interestingly, these arachidonate metabolites were reported to exert a specific role in cancer. Indeed, 5-oxoETE which is the most recently characterized arachidonic acid metabolite, has been found not only to stimulate chemotaxis of white blood cells but also to play a role in cancer, by increasing cell growth and migration of different cancer cell types (Grant et al., 2009), including prostate cancer cells (Powell and Rokach, 2015). Its actions are primarily mediated via the oxoeicosanoid receptor 1 (OXER1, GPR170) which is a G protein coupled receptor, with the G protein complex composed of the Gαi subunit and the Gβγ complex. OXER1 is expressed in white blood cells like neutrophils and eosinophils, lung, liver, kidney and spleen as well as in different neoplastic tumors and cell lines (O'Flaherty et al., 2005, Sarveswaran and Ghosh, 2013). However, the role of this receptor and its significance in cancer has not been elucidated yet. In details, OXER1 activation is accompanied by inhibition of cyclic AMP, due to its coupling to Gαi/ο protein, and an increased Ca2+ mobilization as well as activation of PI3K, Akt and ERK1/2 and PKCδ and ζ (Grant et al., 2009, O'Flaherty et al., 2005, Hosoi et al., 2005, Langlois et al., 2009). In a recent work of our group (Kalyvianaki et al., 2017) in the search of the molecular counterpart of testosterone at the membrane level, we have identified that androgens can interact with OXER1 and mediate at least some of their membrane initiated effects. Androgen can bind to the same molecular groove of the receptor as 5-oxoHETE. However, this binding leads to antagonistic effects, such as the leverage of the inhibitory effect of 5-oxoETE on cAMP production and the opposite action on several intracellular signaling kinases, including Akt, p38α, FAK, MEK/ERK, and JNK. Finally, 5-oxoETE and testosterone have opposing effect on actin cytoskeleton rearrangement and subsequently on cell migration. Under this scope, androgen can therefore be an endogenous disrupting system of lipid-mediated signaling cascades and actions. Interestingly, OXER1 is expressed in the prostate, independently of the presence of intracellular AR and in parallel with the previously reported expression of membrane androgen sites (Dambaki et al., 2005). The potential role of 5-oxoETE and subsequently OXER1 in prostate cancer was further revealed by the inhibition of 5-oxoETE production, through inhibition of 5-LOX enzyme; it was shown that such an inhibition results in apoptosis of prostate cancer cells (Sarveswaran and Ghosh, 2013), an effect shared by membrane-acting androgen (Hatzoglou et al., 2005, Kampa et al., 2005, Kampa et al., 2006).