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Search results for: Androgen Receptor , Mouse

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#34547140   // To Up

Androgen-induced insulin resistance is ameliorated by deletion of hepatic androgen receptor in females.

Androgen excess is one of the most common endocrine disorders of reproductive-aged women, affecting up to 20% of this population. Women with elevated androgens often exhibit hyperinsulinemia and insulin resistance. The mechanisms of how elevated androgens affect metabolic function are not clear. Hyperandrogenemia in a dihydrotestosterone (DHT)-treated female mouse model induces whole body insulin resistance possibly through activation of the hepatic androgen receptor (AR). We investigated the role of hepatocyte AR in hyperandrogenemia-induced metabolic dysfunction by using several approaches to delete hepatic AR via animal-, cell-, and clinical-based methodologies. We conditionally disrupted hepatocyte AR in female mice developmentally (LivARKO) or acutely by tail vein injection of an adeno-associated virus with a liver-specific promoter for Cre expression in AR mice (adLivARKO). We observed normal metabolic function in littermate female Control (AR ) and LivARKO (AR ; Cre ) mice. Following chronic DHT treatment, female Control mice treated with DHT (Con-DHT) developed impaired glucose tolerance, pyruvate tolerance, and insulin tolerance, not observed in LivARKO mice treated with DHT (LivARKO-DHT). Furthermore, during an euglycemic hyperinsulinemic clamp, the glucose infusion rate was improved in LivARKO-DHT mice compared to Con-DHT mice. Liver from LivARKO, and primary hepatocytes derived from LivARKO, and adLivARKO mice were protected from DHT-induced insulin resistance and increased gluconeogenesis. These data support a paradigm in which elevated androgens in females disrupt metabolic function via hepatic AR and insulin sensitivity was restored by deletion of hepatic AR.
Stanley Andrisse, Mingxiao Feng, Zhiqiang Wang, Olubusayo Awe, Lexiang Yu, Haiying Zhang, Sheng Bi, Hongbing Wang, Linhao Li, Serene Joseph, Nicola Heller, Franck Mauvais-Jarvis, Guang William Wong, James Segars, Andrew Wolfe, Sara Divall, Rexford Ahima, Sheng Wu

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#34545067   2021/09/20 To Up

Targeting the Lnc-OPHN1-5/androgen receptor/hnRNPA1 complex increases Enzalutamide sensitivity to better suppress prostate cancer progression.

Long non-coding RNAs (lncRNAs) have been found to play critical roles in regulating gene expression, but their function in translational control is poorly understood. We found lnc-OPHN1-5, which lies close to the androgen receptor (AR) gene on chromosome X, increased prostate cancer (PCa) Enzalutamide (Enz) sensitivity via decreasing AR protein expression and associated activity. Mechanism dissection revealed that lnc-OPHN1-5 interacted with AR-mRNA to minimize its interaction with the RNA binding protein (RBP) hnRNPA1. Suppressing lnc-OPHN1-5 expression promoted the interaction between AR-mRNA and hnRNPA1, followed by an increase of ribosome association with AR-mRNA and translation. This effect was reversed by increasing lnc-OPHN1-5 expression. Consistently, the in vivo mice model confirmed that knocking down lnc-OPHN1-5 expression in tumors significantly increased the tumor formation rate and AR protein expression compared with the control group. Furthermore, knocking down hnRNPA1 blocked/reversed shlnc-OPHN1-5-increased AR protein expression and re-sensitized cells to Enz treatment efficacy. Evidence from Enz-resistant cell lines, patient-derived xenograft (PDX) models, clinical samples, and a human PCa study accordantly suggested that patients with low expression of lnc-OPHN1-5 likely have unfavorable prognoses and probably are less sensitive to Enz treatment. In summary, targeting this newly identified lnc-OPHN1-5/AR/hnRNPA1 complex may help develop novel therapies to increase Enz treatment sensitivity for suppressing the PCa at an advanced stage.
Meng Zhang, Yin Sun, Chi-Ping Huang, Jie Luo, Li Zhang, Jialin Meng, Chaozhao Liang, Chawnshang Chang

2434 related Products with: Targeting the Lnc-OPHN1-5/androgen receptor/hnRNPA1 complex increases Enzalutamide sensitivity to better suppress prostate cancer progression.

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#34541031   2021/08/25 To Up

Human urogenital sinus mesenchyme is an inducer of prostatic epithelial development.

To determine whether human fetal urogenital sinus mesenchyme (UGM) can induce prostatic development in a responsive mouse epithelium.
Gerald R Cunha, Mei Cao, Amber Derpinghaus, Laurence S Baskin

2453 related Products with: Human urogenital sinus mesenchyme is an inducer of prostatic epithelial development.

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#34536356   2021/09/15 To Up

Androgen-deprivation induced senescence in prostate cancer cells is permissive for the development of castration-resistance but susceptible to senolytic therapy.

Prostate cancer (PCa) is one of the leading causes of cancer-related deaths in men. Although androgen deprivation therapies (ADT) and antiandrogens confer increased survival rates, most patients eventually develop castration resistant disease (CRPC). Previous studies have shown that these treatments have limited cytotoxicity, and instead, promote tumor cell growth arrest. We show here that PCa cells grown in either charcoal-stripped serum or exposed to the antiandrogen, bicalutamide, undergo a senescent growth arrest marked by morphological changes, upregulated senescence-associated-β-galactosidase (SA-β-Gal), cathepsin D accumulation, and expression of the senescence-associated secretory phenotype (SASP). The senescent growth arrest is, however, transient, as cells can resume proliferation upon restoration of normo-androgenic conditions. Intriguingly, enrichment for senescent cells confirmed that ADT-induced senescent cells recover their proliferative capacity, even under prolonged androgen deprivation, and form androgen-independent outgrowths. Transplantation of the enriched senescent population into castrated, syngeneic mice confirmed that senescent cells escape arrest and form castration-resistant tumors in vivo. Outgrowth from senescence was associated with increased expression of constitutively active androgen receptor splice variants, a common mechanism of resistance to ADT. Finally, the selective elimination of senescent PCa cells following ADT in vitro by the senolytic navitoclax (ABT-263) interfered with the development of androgen-independent outgrowth. Taken together, these data support the premise that ADT-induced senescence is a transient cell state from which CRPC populations can emerge, identifying senescence as a potential driver of disease progression. Furthermore, it is feasible that senolytic therapy to eliminate senescent PCa cells could delay disease recurrence and/or progression to androgen independence.
Valerie Carpenter, Tareq Saleh, So Min Lee, Graeme Murray, Jason Reed, Andrew Souers, Anthony Faber, Hisashi Harada, David A Gewirtz

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#34529765   2021/09/16 To Up

Reproductive Deficits Induced by Prenatal Anti-Mullerian Hormone Exposure Require Androgen Receptor in Kisspeptin Cells.

Polycystic ovary syndrome (PCOS) is a common reproductive disorder characterized by elevated androgens and anti-Mullerian hormone (AMH). These hormones remain elevated throughout pregnancy, and potential effects of hormone exposure on offspring from women with PCOS remain largely unexplored. Expanding on recent reports of prenatal AMH exposure in mice, we have fully characterized the reproductive consequences of prenatal AMH (pAMH) exposure throughout the lifespan of first- and second-generation offspring of both sexes. We also sought to elucidate mechanisms underlying pAMH-induced reproductive effects. There is a known reciprocal relationship between AMH and androgens, and in PCOS and PCOS-like animal models, androgen feedback is dysregulated at the level the hypothalamus. Kisspeptin neurons express androgen receptors and play a critical role in sexual development and function. We therefore hypothesized that pAMH-induced reproductive phenotypes would be mediated by androgen signaling at the level of kisspeptin cells. We tested the pAMH model in kisspeptin-specific androgen receptor knockout (KARKO) mice and found that virtually all pAMH-induced phenotypes assayed are eliminated in KARKO offspring compared to littermate controls. By demonstrating the necessity of androgen receptor in kisspeptin cells to induce pAMH phenotypes, we have advanced understanding of the interactions between AMH and androgens in the context of prenatal exposure, which could have significant implications for children of women with PCOS.
Emily V Ho, Chengxian Shi, Jessica Cassin, Michelle Y He, Ryan D Nguyen, Genevieve E Ryan, Karen J Tonsfeldt, Pamela L Mellon

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#34503965   2021/09/09 To Up

Prenatal androgen treatment does not alter the firing activity of hypothalamic arcuate kisspeptin neurons in female mice.

Neuroendocrine control of reproduction is disrupted in many individuals with polycystic ovary syndrome, who present with increased luteinizing hormone (LH), and presumably gonadotropin-releasing hormone (GnRH), release frequency, and high androgen levels. Prenatal androgenization (PNA) recapitulates these phenotypes in primates and rodents. Female offspring of mice injected with dihydrotestosterone (DHT) on gestational D16-18 exhibit disrupted estrous cyclicity, increased LH and testosterone, and increased GnRH neuron firing rate as adults. PNA also alters the developmental trajectory of GnRH neuron firing rates, markedly blunting the prepubertal peak in firing that occurs in 3wk-old controls. GnRH neurons do not express detectable androgen receptors and are thus probably not the direct target of DHT. Rather, PNA likely alters GnRH neuronal activity by modulating upstream neurons, such as hypothalamic arcuate neurons co-expressing kisspeptin, neurokinin B (gene Tac2), and dynorphin, aka KNDy neurons. We hypothesized PNA treatment changes firing rates of KNDy neurons in a similar age-dependent manner as GnRH neurons. We conducted targeted extracellular recordings (0.5-2h) of Tac2-identified KNDy neurons from control and PNA mice at 3wks of age and in adulthood. About half of neurons were quiescent (<0.005Hz). Long-term firing rates of active cells varied, suggestive of episodic activity, but were not different among groups. Short-term burst firing was also similar. We thus reject the hypothesis that PNA alters the firing rate of KNDy neurons. This does not preclude altered neurosecretory output of KNDy neurons, involvement of other neuronal populations, or networks as critical drivers of altered GnRH firing rates in PNA mice.Prenatal androgenization (PNA) recapitulates key aspects of the common reproductive disorder polycystic ovary syndrome. It is postulated that disruptions in the episodic pattern of gonadotropin-releasing hormone (GnRH) secretion in part underly this disorder, yet GnRH neurons do not express androgen receptor to respond directly to elevated androgens. A population of kisspeptin, neurokinin B, and dynorphin-expressing (KNDy) neurons in the hypothalamic arcuate nucleus are thought to regulate pulsatile GnRH release and some express androgen receptor. We did not find evidence, however, that PNA altered spontaneous activity of KNDy neurons before puberty at 3wks of age or in adulthood. This suggests that PNA likely acts through other components of the broader hypothalamic network to change the patterns of GnRH release.
Amanda G Gibson, Jennifer Jaime, Laura L Burger, Suzanne M Moenter

1011 related Products with: Prenatal androgen treatment does not alter the firing activity of hypothalamic arcuate kisspeptin neurons in female mice.

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#34503116   2021/08/26 To Up

Identification of Androgen Receptor Metabolic Correlome Reveals the Repression of Ceramide Kinase by Androgens.

Prostate cancer (PCa) is one of the most prevalent cancers in men. Androgen receptor signaling plays a major role in this disease, and androgen deprivation therapy is a common therapeutic strategy in recurrent disease. Sphingolipid metabolism plays a central role in cell death, survival, and therapy resistance in cancer. Ceramide kinase (CERK) catalyzes the phosphorylation of ceramide to ceramide 1-phosphate, which regulates various cellular functions including cell growth and migration. Here we show that activated androgen receptor (AR) is a repressor of expression. We undertook a bioinformatics strategy using PCa transcriptomics datasets to ascertain the metabolic alterations associated with AR activity. was among the most prominent negatively correlated genes in our analysis. Interestingly, we demonstrated through various experimental approaches that activated AR reduces the mRNA expression of : (i) expression of is predominant in cell lines with low or negative AR activity; (ii) AR agonist and antagonist repress and induce mRNA expression, respectively; (iii) orchiectomy in wildtype mice or mice with PCa (harboring prostate-specific deletion) results in elevated mRNA levels in prostate tissue. Mechanistically, we found that AR represses through interaction with its regulatory elements and that the transcriptional repressor EZH2 contributes to this process. In summary, we identify a repressive mode of AR that influences the expression of in PCa.
Laura Camacho, Amaia Zabala-Letona, Ana R Cortazar, Ianire Astobiza, Asier Dominguez-Herrera, Amaia Ercilla, Jana Crespo, Cristina Viera, Sonia Fernández-Ruiz, Ainara Martinez-Gonzalez, Veronica Torrano, Natalia Martín-Martín, Antonio Gomez-Muñoz, Arkaitz Carracedo

2844 related Products with: Identification of Androgen Receptor Metabolic Correlome Reveals the Repression of Ceramide Kinase by Androgens.

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#34496233   // To Up

Reshaping of the androgen-driven chromatin landscape in normal prostate cells by early cancer drivers and effect on therapeutic sensitivity.

The normal androgen receptor (AR) cistrome and transcriptional program are fundamentally altered in prostate cancer (PCa). Here, we profile the chromatin landscape and AR-directed transcriptional program in normal prostate cells and show the impact of SPOP mutations, an early event in prostate tumorigenesis. In genetically normal mouse prostate organoids, SPOP mutation results in accessibility and AR binding patterns similar to that of human PCa. Consistent with dependence on AR signaling, castration of SPOP mutant mouse models results in the loss of neoplastic phenotypes, and human SPOP mutant PCa shows a favorable response to AR-targeted therapies. Together, these data validate mouse prostate organoids as a robust model for studying epigenomic and transcriptional alterations in normal prostate, provide valuable datasets for further studies, and show that a single genomic alteration may be sufficient to reprogram the chromatin of normal prostate cells toward oncogenic phenotypes, with potential therapeutic implications for AR-targeting therapies.
Ivana Grbesa, Michael A Augello, Deli Liu, Dylan R McNally, Christopher D Gaffney, Dennis Huang, Kevin Lin, Daria Ivenitsky, Ramy Goueli, Brian D Robinson, Francesca Khani, Lesa D Deonarine, Mirjam Blattner, Olivier Elemento, Elai Davicioni, Andrea Sboner, Christopher E Barbieri

2333 related Products with: Reshaping of the androgen-driven chromatin landscape in normal prostate cells by early cancer drivers and effect on therapeutic sensitivity.



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#34480994   2021/09/02 To Up

Crocus sativus (saffron) petals extract and its active ingredient, anthocyanin improves ovarian dysfunction, regulation of inflammatory genes and antioxidant factors in testosterone-induced PCOS mice.

Saffron petal has traditionally been used to treat a variety of diseases, such as gynecological disease such as primary dysmenorrhea and premenstrual tension. Polycystic Ovary Syndrome (PCOS) is a form of gynecological disease that causes amenorrhea, infertility, menopausal and urogenital disorders. This disease may be treated with saffron petals.
Fazeleh Moshfegh, Saeedeh Zafar Balanejad, Khadige Shahrokhabady, Armin Attaranzadeh

2840 related Products with: Crocus sativus (saffron) petals extract and its active ingredient, anthocyanin improves ovarian dysfunction, regulation of inflammatory genes and antioxidant factors in testosterone-induced PCOS mice.

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#34475205   // To Up

AR-negative prostate cancer is vulnerable to loss of JMJD1C demethylase.

Prostate cancer is a leading cause of cancer-related mortality in men. The widespread use of androgen receptor (AR) inhibitors has generated an increased incidence of AR-negative prostate cancer, triggering the need for effective therapies for such patients. Here, analysis of public genome-wide CRISPR screens in human prostate cancer cell lines identified histone demethylase JMJD1C (KDM3C) as an AR-negative context-specific vulnerability. Secondary validation studies in multiple cell lines and organoids, including isogenic models, confirmed that small hairpin RNA (shRNA)-mediated depletion of JMJD1C potently inhibited growth specifically in AR-negative prostate cancer cells. To explore the cooperative interactions of AR and JMJD1C, we performed comparative transcriptomics of 1) isogenic AR-positive versus AR-negative prostate cancer cells, 2) AR-positive versus AR-negative prostate cancer tumors, and 3) isogenic JMJD1C-expressing versus JMJD1C-depleted AR-negative prostate cancer cells. Loss of AR or JMJD1C generates a modest tumor necrosis factor alpha (TNFα) signature, whereas combined loss of AR and JMJD1C strongly up-regulates the TNFα signature in human prostate cancer, suggesting TNFα signaling as a point of convergence for the combined actions of AR and JMJD1C. Correspondingly, AR-negative prostate cancer cells showed exquisite sensitivity to TNFα treatment and, conversely, TNFα pathway inhibition via inhibition of its downstream effector MAP4K4 partially reversed the growth defect of JMJD1C-depleted AR-negative prostate cancer cells. Given the deleterious systemic side effects of TNFα therapy in humans and the viability of JMJD1C-knockout mice, the identification of JMJD1C inhibition as a specific vulnerability in AR-negative prostate cancer may provide an alternative drug target for prostate cancer patients progressing on AR inhibitor therapy.
Yohei Yoshihama, Kyle A LaBella, Eiru Kim, Lori Bertolet, Medina Colic, Jiexi Li, Xiaoying Shang, Chang-Jiun Wu, Denise J Spring, Y Alan Wang, Traver Hart, Ronald A DePinho

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