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Androgen Receptors

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Christos Stournaras – One of the best experts on this subject based on the ideXlab platform.

  • activation of membrane Androgen Receptors in colon cancer inhibits the prosurvival signals akt bad in vitro and in vivo and blocks migration via vinculin actin signaling
    Molecular Medicine, 2011
    Co-Authors: Natalia Papadopoulou, Christos Stournaras, Omaima Nasir, Michael Foller, Konstantinos Alevizopoulos, Florian Lang


    Recently, we reported that membrane Androgen Receptors (mARs) are expressed in colon tumors triggering strong apoptotic responses. In the present study, we analyzed mAR-induced downstream effectors controlling cell survival and migration of Caco2 colon cancer cells. We show that long-term activation of mAR downregulated the activity of PI-3K and Akt and induced dephosphorylation/activation of the proapoptotic Bad (p-Bad). Moreover, treatment of APCMin/+ mice, which spontaneously develop intestinal tumors, with mAR-activating testosterone conjugates reduced the tumor incidence by 80% and significantly decreased the expression of p-Akt and p-Bad levels in tumor tissue. Furthermore, mAR activation strongly inhibited Caco2 cell migration. In accordance with these findings, vinculin, a protein controlling cell adhesion and actin reorganization, was effectively phosphorylated upon mAR activation. Phosphorylation inhibitors genistein and PP2 inhibited actin reorganization and restored motility. Moreover, silencing vinculin by appropriate siRNA’s, or blocking actin reorganization by cytochalasin B, restored the migration potential. From these results we conclude that mAR activation inhibits the prosurvival signals Akt/Bad in vitro and in vivo and blocks migration of colon cancer cells via regulation of vinculin signaling and actin reorganization, supporting the powerful tumoristatic effect of those Receptors.

  • functional membrane Androgen Receptors in colon tumors trigger pro apoptotic responses in vitro and reduce drastically tumor incidence in vivo
    Molecular Cancer, 2009
    Co-Authors: Natalia Papadopoulou, Christos Stournaras, Evamaria Gehring, Omaima Nasir, Konstantinos Dimas, Shefalee K Bhavsar, Michael Foller, Konstantinos Alevizopoulos, Florian Lang


    Membrane Androgen Receptors (mAR) have been implicated in the regulation of cell growth, motility and apoptosis in prostate and breast cancer. Here we analyzed mAR expression and function in colon cancer.

  • Activation of membrane Androgen Receptors potentiates the antiproliferative effects of paclitaxel on human prostate cancer cells.
    Molecular Cancer Therapeutics, 2006
    Co-Authors: Marilena Kampa, Christina Kogia, Christos Stournaras, Panayiotis A Theodoropoulos, Ploutarchos Anezinis, Ioannis Charalampopoulos, Evangelia A Papakonstanti, Efstathios N Stathopoulos, Anastassia Hatzoglou, Achille Gravanis


    Genomic signaling mechanisms require a relatively long time to get into action and represent the main way through which steroid hormones affect target cells. In addition, steroids may rapidly activate cellular functions by non-genomic signaling mechanisms involving membrane sites. Understanding in depth the molecular mechanisms of the non-genomic action represents an important frontier for developing new and more selective pharmacologic tools for endocrine therapies. In the present study, we report that membrane-impermeable testosterone-bovine serum albumin (BSA) acts synergistically with paclitaxel in modifying actin and tubulin cytoskeleton dynamics in LNCaP (Androgen sensitive) and DU-145 (Androgen insensitive) human prostate cancer cell lines. In addition, coincubation of either cell line with testosterone-BSA and paclitaxel induced inhibition of cell proliferation and apoptosis. Finally, in vivo experiments in LNCaP and DU-145 tumor xenografts in nude mice showed that both agents decrease tumor mass, whereas testosterone-BSA enhances the effect of paclitaxel. Our findings suggest that chronic activation of membrane Androgen Receptors in vitro and in vivo facilitates and sustains for a longer time the antitumoral action of cytoskeletal acting agents.

A Hobisch – One of the best experts on this subject based on the ideXlab platform.

  • Androgen Receptors in prostate cancer
    The Journal of Urology, 2003
    Co-Authors: Zoran Culig, Helmut Klocker, Georg Bartsch, Hannes Steiner, A Hobisch


    ABSTRACTPurpose: Androgen receptor (AR) is expressed in the majority of human prostate cancers. For a better understanding of prostate carcinoma events it is necessary to present findings on the regulation of AR target genes, AR interaction with associated proteins, ligand independent activation and point mutations.Materials and Methods: A comprehensive literature review of manuscripts published on AR in prostate cancer was performed using PubMed.Results: AR regulates the expression of genes involved in the proliferation and differentiation of prostate cancer cells. Due to differential interactions with coactivators and corepressors AR activation results in the stimulation of a mitogenic response or in the expression of secretory proteins. AR is functional in advanced carcinoma of the prostate, as evidenced in studies of mutant Receptors and ligand independent activation. AR point mutations appear in advanced prostate cancer more frequently than in organ confined disease.Conclusions: Current therapy optio…

  • Androgen Receptors in prostate cancer
    Endocrine-related Cancer, 2002
    Co-Authors: Zoran Culig, Helmut Klocker, Georg Bartsch, A Hobisch


    The Androgen receptor (AR), a transcription factor that mediates the action of Androgens in target tissues, is expressed in nearly all prostate cancers. Carcinoma of the prostate is the most frequently diagnosed neoplasm in men in industrialized countries. Palliative treatment for non-organ-confined prostate cancer aims to down-regulate the concentration of circulating Androgen or to block the transcription activation function of the AR. AR function during endocrine therapy was studied in tumor cells LNCaP subjected to long-term steroid depletion; newly generated sublines could be stimulated by lower concentrations of Androgen than parental cells and showed up-regulation of AR expression and activity as well as resistance to apoptosis. Androgenic hormones regulate the expression of key cell cycle regulators, cyclin-dependent kinase 2 and 4, and that of the cell cycle inhibitor p27. Inhibition of AR expression could be achieved by potential chemopreventive agents flufenamic acid, resveratrol, quercetin, polyunsaturated fatty acids and interleukin-1β, and by the application of AR antisense oligonucleotides. In the clinical situation, AR gene amplification and point mutations were reported in patients with metastatic disease. These mutations generate Receptors which could be activated by other steroid hormones and non-steroidal antiAndrogens. In the absence of Androgen, the AR could be activated by various growth-promoting (growth factors, epidermal growth factor receptor-related oncogene HER-2/neu) and pleiotropic (protein kinase Aactivators, interleukin-6) compounds as well as by inducers of differentiation (phenylbutyrate). AR function is modulated by a number of coactivators and corepressors. The three coactivators, TIF-2, SRC-1 and RAC3, are up-regulated in relapsed prostate cancer. New experimental therapies for prostate cancer are aimed to down-regulate AR expression and to overcome difficulties which occur because of the acquisition of agonistic properties of commonly used antiAndrogens. Endocrine-Related Cancer (2002) 9 155–170

Marc S Breedlove – One of the best experts on this subject based on the ideXlab platform.

  • Androgen Receptors mediate masculinization of astrocytes in the rat posterodorsal medial amygdala during puberty
    The Journal of Comparative Neurology, 2013
    Co-Authors: Ryan T Johnson, Marc S Breedlove, Cynthia L Jordan


    Astrocytes in the posterodorsal portion of the medial amygdala (MePD) are sexually dimorphic in adult rats: males have more astrocytes in the right MePD and more elaborate processes in the left MePD than do females. Functional Androgen Receptors (ARs) are required for masculinization of MePD astrocytes, as these measures are demasculinized in adult males carrying the testicular feminization mutation (Tfm) of the AR gene, which renders AR dysfunctional. We now report that the number of astrocytes is already sexually dimorphic in the right MePD of juvenile 25-day-old (P25) rats. Because Tfm males have as many astrocytes as wild-type males at this age, this prepubertal sexual dimorphism is independent of ARs. After P25, astrocyte number increases in the MePD of all groups, but activation of ARs augments this increase in the right MePD, where more astrocytes are added in males than in Tfm males. Consequently, by adulthood, females and Tfm males have equivalent numbers of astrocytes in the right MePD. Sexual dimorphism in astrocyte arbor complexity in the left MePD arises after P25, and is entirely AR-dependent. Thus, masculinization of MePD astrocytes is a result of both AR-independent processes before the juvenile period and AR-dependent processes afterward. J. Comp. Neurol. 521:2298–2309, 2013. © 2012 Wiley Periodicals, Inc.

  • the role of Androgen Receptors in the masculinization of brain and behavior what we ve learned from the testicular feminization mutation
    Hormones and Behavior, 2008
    Co-Authors: Damian G Zuloaga, David A Puts, Cynthia L Jordan, Marc S Breedlove


    Many studies demonstrate that exposure to testicular steroids such as testosterone early in life masculinizes the developing brain, leading to permanent changes in behavior. Traditionally, masculinization of the rodent brain is believed to depend on estrogen Receptors (ERs) and not Androgen Receptors (ARs). According to the aromatization hypothesis, circulating testosterone from the testes is converted locally in the brain by aromatase to estrogens, which then activate ERs to masculinize the brain. However, an emerging body of evidence indicates that the aromatization hypothesis cannot fully account for sex differences in brain morphology and behavior, and that Androgens acting on ARs also play a role. The testicular feminization mutation (Tfm) in rodents, which produces a nonfunctional AR protein, provides an excellent model to probe the role of ARs in the development of brain and behavior. Tfm rodent models indicate that ARs are normally involved in the masculinization of many sexually dimorphic brain regions and a variety of behaviors, including sexual behaviors, stress response and cognitive processing. We review the role of ARs in the development of the brain and behavior, with an emphasis on what has been learned from Tfm rodents as well as from related mutations in humans causing complete Androgen insensitivity.

  • both estrogen Receptors and Androgen Receptors contribute to testosterone induced changes in the morphology of the medial amygdala and sexual arousal in male rats
    Hormones and Behavior, 2003
    Co-Authors: Bradley M Cooke, Marc S Breedlove, Cynthia L Jordan


    Abstract In male rats, a steroid-sensitive circuit in the forebrain regulates mating behavior. The masculine phenotype in one component of the circuit, the posterodorsal nucleus of the medial amygdala (MePD), depends on the level of circulating Androgens in the adult. To investigate which gonadal steroid receptor(s) mediate sexual arousal and MePD plasticity, adult male rats were castrated and given Silastic capsules containing the nonaromatizable Androgen 5α-dihydrotestosterone (DHT), 17β-estradiol (E2), both steroids, or nothing. A fifth group was sham-castrated and treated with blank capsules. DHT treatment was necessary and sufficient to maintain the expression of noncontact penile erections and ultrasonic vocalizations in castrates. E2 had no significant effect on these measures. Both DHT and E2 increased olfactory investigation (“nosepokes”) during the noncontact penile erection test. E2, but not DHT, maintained intromission patterns, while either steroid, alone or in combination, maintained ejaculatory behavior. Regional volume and cell soma size of the MePD both decreased following castration. Additionally, MePD cell size was lateralized, with left hemisphere neurons larger than those on the right, an effect that appeared independent of steroid manipulations. DHT and E2 each maintained neuronal soma size. E2 maintained MePD regional volume more effectively in the left MePD than in the right, which may have been due to a greater sensitivity of the left to both castration and hormone treatment. Thus, both Androgen Receptors and estrogen Receptors appear to participate in sexual behaviors that may be mediated by the MePD in adult rats, and both Receptors contribute to the steroid-regulated structural plasticity in this brain region.