This unsuspected antagonistic interaction of androgen with O
This unsuspected antagonistic interaction of androgen with OXER1 could therefore explain the effect of plant derived compounds with this ligand-receptor system. For example, wedelolactone, a coumestan found in Eclipta alba (false daisy) and in Wedelia calendulacea that is the major component of eclipta prostrata L (a traditional chinese herbal medicine) has been shown to induce apoptosis of prostate cancer cells by interfering with 5-LOX activity that generates 5-oxoETE, which via OXER1 promotes cell survival (Sarveswaran et al., 2012). In fact, such an interaction could provide an alternative mechanism for the action of a number of plant-derived agents and extracts that have been found to mimic, or interfere with, androgen actions. They are referred with the term phytoandrogens and have been reported to exert androgenic effects even when the classical androgen receptor is not present. Phytoandrogens are quite limited in number and by far less studied compared to their estrogenic counterparts. A representative example could be plant triterpenoids from the tree Annexin V-Cy3 Apoptosis Kit (cortex) of the Gutta-Percha tree Eucommia ulmoides which was the first plant compound shown to exert male hormone-like effects (Ong and Tan, 2007). These compounds have been shown to interact directly with the AR receptor. However, their action was in fact, enhanced when a total extract was tested, by the presence of lipid components. The total extract also increased prostate growth in prepubertal male Wistar rats. A possible explanation for this synergism could be the parallel involvement of the OXER1 receptor in both actions.
A schematic representation of the majority of plant derived compounds which have been identified so far, to disrupt androgen action, along with their specific site of action within the cell is given in Fig. 1.
Conclusions-further perspectives Androgen have not attracted the interest attributed to estrogen, until recently. This is mainly due to the “simpler” physiology of prostate cancer, as compared to ER-related breast and ovarian cancers. However, recent advances in AR physiology and function, together with the identification of ligand-dependent and independent AR splice variants and the identification of extra-nuclear and membrane-initiated AR actions have booster the scientific and translational interest to this receptor. The emergence of phyto- and xeno-androgen, the identification of a number of membrane GPCRs with AR-binding activity (ZIP9 (Thomas et al., 2014), GPRC6A (Pi et al., 2010, Pi and Quarles, 2012) and OXER1, as presented here) and the notion that the biology of castration-resistant (hormone-independent) prostate cancer is due to an extreme sensitivity rather than to the lack of ARs (see Pelekanou and Castanas, 2016, and Pelekanou et al., 2007), for a discussion on the subject) have propagated the interest on this receptor. In addition, as briefly reported above, the discovery of an androgen-induced disruption of lipid signaling, as well as the existence of phyto-androgen with specific lipid-mediated action provides clues about the possible physiological significance of these chemicals. However, this subject is very novel and subsequent research is needed to confirm the role of plant- or chemical-derived substances with specific actions on cancer cell growth (initiation and progression), through multiple mechanisms.
Introduction In contrast to numerous other malignancies, the incidence of prostate cancer, which is the most common cancer in men, is not increased in case of concurrent type 2 diabetes mellitus; several studies even reported a decreased risk . One of the crucial drivers for prostate cell growth is androgen signaling, paving the way for the androgen-deprivation therapy (ADT) as one standard treatment for prostate cancer . Recently, it was shown that increasing glucose concentrations are able to downregulate androgen receptor (AR) mRNA and protein levels through NF-kB activation in vitro and in an animal model of prostate cancer . Given that men with type 2 diabetes have lower testosterone levels per se, the mentioned changes could be one possible explanation for the lower prostate cancer incidence in this patient group . Nevertheless, according to numerous previous studies, prostate cancer survival is clearly reduced when type 2 diabetes is present [5–7]. Although strong epidemiological evidence links prostate cancer and type 2 diabetes, the underlying molecular mechanisms are still not understood in detail.