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  • A number of studies indicate

    2023-01-10

    A number of studies indicate the involvement of the classical AR or a splice variant that translocate to the membrane, via a palmitoylation mechanism, similar to ERα (Acconcia et al., 2005, Acconcia et al., 2004, Acconcia et al., 2003), since AR equally contains the required nine amino ZSTK474 synthesis palmitoylation motif (Pedram et al., 2007, Yang et al., 2011). However, there are data that support the involvement of (a) different protein(s) at the membrane level. These include the inability of classical androgen receptor antagonists, such as flutamide or cyproterone acetate, to inhibit membrane initiated androgen actions (Hatzoglou et al., 2005, Kampa et al., 2002), the existence of such actions in cells lacking classical AR (Nifli et al., 2005) and their blockade with pertussis toxin that indicates a GPCR participation (Sun et al., 2006). Our team being actively involved in the field of extra-nuclear steroid actions and especially that of androgens in prostate and breast cancer, have reported for the first time the presence of androgen membrane binding sites in prostate and breast cancer cell lines (Kampa et al., 2002, Kampa et al., 2005), patients’ isolated neoplastic cells (Stathopoulos et al., 2003) and tissue specimens (Dambaki et al., 2005). Activation of these sites initially triggers rapid Ca2+ movements, signaling molecule activation, leading to cytoskeletal changes and modulating secretion (Papakonstanti et al., 2003). At a second step, these rapid actions lead to specific transcriptional effects (Notas et al., 2010) and activation of molecules leading to apoptosis (Hatzoglou et al., 2005). We have therefore proposed the targeting of these membrane sites as novel, potential, therapeutic approach in prostate cancer therapeutics (Kampa et al., 2006). Taking into consideration this membrane initiated mode of action for androgens, we have found that the naturally occurring flavanols catechin and epicatechin and their dimers B2 and B5 (oligomeric procyanydins, OPCs) can act as small-molecular agonists of mAR, representing promising anti-tumoral agents both in breast and prostate cancer. Specifically, we have reported that B2 OPC (4β-8 epicatechin dimer) can bind to membrane androgen binding sites trigger the same signaling cascades with membrane acting testosterone (testosterone-BSA) resulting in actin cytoskeleton rearrangements and apoptosis of breast and prostate cancer cells (Nifli et al., 2005, Kampa et al., 2011). The latter represents an alternative way that natural, plant derived ligands can interfere with androgen hormonal action, not only by modulating their classical mode of action in which AR has a central role acting as a transcription factor, but also by changing extranuclear, membrane initiated cell responses.
    Natural agents and androgen signaling interference Several natural agents have been described to interfere with different kinases representing an alternative way for natural agents to modulate extranuclear androgen actions. These kinases are either involved in the membrane initiated androgen signaling pathways or in the downstream signaling of different cytokine or growth factor receptors, implicated in the extranuclear androgen receptor activation. Such agents include genistein that has been shown to be a tyrosine kinase inhibitor (inhibiting both receptor tyrosine kinases (RTKs) and non-RTKs, such as src kinase) (Akiyama et al., 1987), daidzein and its metabolite 6,7,4'-trihydroxyisoflavone (6,7,4′-THIF) to inhibit PKCα (Lim et al., 2014), curcumin to inhibit src, focal adhesion kinase (FAK) and PKC (Leu et al., 2003, Reddy and Aggarwal, 1994, Pany et al., 2016), EGCG to inhibit ERK1/2 and Akt (Sah et al., 2004) and resveratrol to inhibit Akt and PKC (Hsieh et al., 2014, Slater et al., 2003), while curcumin was found to interfere with both PI3K/Akt pathways and AR degradation (Rahmani et al., 2014, and references herein).