Identification of the estrogen receptor GPER in neoplastic and non-neoplastic human testes

<p>Abstract</p> <p>Background</p> <p>Estrogen signaling is mediated by estrogen receptor beta isoforms in normal and neoplastic human testes. Recently, a G-protein-coupled-receptor (GPER) has been suggested as being involved in rapid responses to estrogens in different normal and tumor cells.</p> <p>Methods</p> <p>This study investigated the GPER expression in paraffin-embedded samples from non neoplastic and neoplastic human testes (sex-cord stromal and germ cell tumors) by immunohistochemical and Western Blot analyses.</p> <p>Results</p> <p>In control testes, a positive GPER immunoreactivity was detected in Leydig and in Sertoli cells while all germ cells were immunonegative. Furthermore, neoplastic cells of the Sertoli cell tumor, Leydig cell tumor, seminoma and embryonal carcinoma samples were all immunopositive. The immunoblots of testis extracts confirmed the results.</p> <p>Conclusions</p> <p>These findings suggest that GPER could mediate estrogen signaling in both normal and transformed somatic cells of human testis, but they reveal a differential expression of the novel estrogen receptor in non neoplastic and neoplastic germ cells.</p

Bioactive Constituents from the Traditional Kurdish plant Iris persica

In the first phytochemical investigation of non-volatile secondary metabolites from the Kurdish traditional plant Iris persica L, (-)-embinin was isolated from flowers and leaves, isovitexin from flowers, trans-resveratrol-3- O-β-D-glucopyranoside from rhizomes and tectorigenin from bulbs. The complete NMR spectra of embinin are reported for the first time. In an MTT assay, embinin showed an inhibition activity higher than the well-known antitumor drug cisplatin against five of the six tested human tumor cells. Moreover, embinin showed a significant DPPH radical scavenging activity (IC50 value of 112.16) comparable to the reference antioxidant ascorbic acid. The remarkable biological activities exhibited by the extracts of Iris persica and isolated compounds have validated the uses of I. persica in the traditional medicine of Kurdistan

Crucial role of phospholamban phosphorylation and S-nitrosylation in the negative lusitropism induced by 17β-estradiol in the male rat heart.

Background/Aims: 17β-estradiol (17βE2) plays an important cardiovascular role by activating estrogen receptors (ER) α and ERβ. Previous studies demonstrated that the novel estrogen G protein-coupled receptor (GPR30/GPER) mediates estrogen action in different tissues. We have recently shown in the rat heart that 17βE2 elicits negative inotropism through ERα, ERβ and GPR30, by triggering activation of ERK1/2, phosphatidylinositol 3-kinase (PI3K), protein kinase A (PKA) and endothelial Nitric Oxide synthase (eNOS) signaling. Methods: In the present study, using the isolated and Langendorff-perfused rat heart as a model system we analyzed: i) whether and to which extent 17βE2 modifies mammalian ventricular myocardial relaxation (lusitropism); ii) the type of ERs and the signaling pathways involved in this effect. Results: We found that 17βE2 negatively modulated the ventricular lusitropic performance. This effect, which partially involved the vascular endothelium, recruited ERβ and occurred via PI3K, eNOS-NO-cGMP-protein kinase G (PKG) transduction cascade. Of note, 17βE2-mediated negative lusitropism associated with a modification of phospholamban (PLN) phosphorylation and S-nitrosylation (SNO) both in isolated Langendorff rat heart and in isolated cardiomyocytes. Conclusion: Taken together, our results allow including 17βE2 to the family of substances that control ventricular relaxation. This is of relevance in relation not only to the normal endocrine control of cardiac function, but also to physio-pathologic conditions characterized by an altered ventricular diastolic performance

Metformin inhibits androgen-induced IGF-IR up-regulation in prostate cancer cells by disrupting membrane-initiated androgen signaling.

We have previously demonstrated that, in prostate cancer cells, androgens up-regulate IGF-I receptor (IGF-IR) by inducing cAMP-response element-binding protein (CREB) activation and CREB-dependent IGF-IR gene transcription through androgen receptor (AR)-dependent membrane-initiated effects. This IGF-IR up-regulation is not blocked by classical antiandrogens and sensitizes cells to IGF-I-induced biological effects. Metformin exerts complex antitumoral functions in various models and may inhibit CREB activation in hepatocytes. We, therefore, evaluated whether metformin may affect androgen-dependent IGF-IR up-regulation. In the AR(+) LNCaP prostate cancer cells, we found that metformin inhibits androgen-induced CRE activity and IGF-IR gene transcription. CRE activity requires the formation of a CREB-CREB binding protein-CREB regulated transcription coactivator 2 (CRTC2) complex, which follows Ser133-CREB phosphorylation. Metformin inhibited Ser133-CREB phosphorylation and induced nuclear exclusion of CREB cofactor CRTC2, thus dissociating the CREB-CREB binding protein-CRTC2 complex and blocking its transcriptional activity. Similarly to metformin action, CRTC2 silencing inhibited IGF-IR promoter activity. Moreover, metformin blocked membrane-initiated signals of AR to the mammalian target of rapamycin/p70S6Kinase pathway by inhibiting AR phosphorylation and its association with c-Src. AMPK signals were also involved to some extent. By inhibiting androgen-dependent IGF-IR up-regulation, metformin reduced IGF-I-mediated proliferation of LNCaP cells. These results indicate that, in prostate cancer cells, metformin inhibits IGF-I-mediated biological effects by disrupting membrane-initiated AR action responsible for IGF-IR up-regulation and suggest that metformin could represent a useful adjunct to the classical antiandrogen therapy

Fibronectin and type IV collagen activate ERα AF-1 by c-Src pathway: effect on breast cancer cell motility

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Highly Cytotoxic Xanthones from Cratoxylum cochinchinense Collected in Myanmar

Eight xanthones and one anthraquinone, together with four common triterpenoids, have been isolated from the barks of Cratoxylum cochinchinense, collected in Myanmar. The structures of the metabolites were elucidated by spectroscopic data analysis and their antiproliferative activities were measured against six human tumor cell lines, by using the MTT assay. Pruniflorone N (1) showed a significant cytotoxicity against all cancer cells with IC50 values in the range 3-9 μM, on average higher than the anticancer drug cisplatin. Instead, compounds 2 and 3 exhibited high antiproliferative activity against some specific cell lines

Synthesis, characterization and cytotoxic activity on breast cancer cells of new half-titanocene derivatives

A series of novel titanocene-complexes has been prepared and evaluated for their growth regulatory effects in MCF7 and SkBr3 breast cancer cells. The capability of some of these compound to elicit relevant repressive effects on cancer cell growth could be taken into account towards novel pharmacological approaches in cancer therapy

Differential phosphorylation of c-Jun and JunD in response to the epidermal growth factor is determined by the structure of MAPK targeting sequences

MAPK phosphorylation of various substrates is mediated by the presence of docking sites, including the D domain and the DEF motif. Depending on the number and sequences of these domains, substrates are phosphorylated by specific subsets of MAPKs. For example, a D domain targets JNK to c-Jun, whereas a DEF motif is required for ERK phosphorylation of c-Fos. JunD, in contrast, contains both D and DEF domains. Here we show that these motifs mediate JunD phosphorylation in response to either ERK or JNK activation. An intact D domain is required for phosphorylation and activation of JunD by both subtypes of MAPK. The DEF motif acts together with the D domain to elicit efficient phosphorylation of JunD in response to the epidermal growth factor (EGF) but has no function on JunD phosphorylation and activation by JNK signaling. Furthermore, we show that conversion of a c-Jun sequence to a canonical DEF domain, as it is present in JunD, elicits c-Jun activation in response to EGF. Our results suggest that evolution of a particular modular system of MAPK targeting sequences has determined a differential response of JunD and c-Jun to ERK activation

Menin uncouples Elk-1, JunD and c-Jun phosphorylation from MAP kinase activation

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