-
Clinical Cancer Research : An Official... Apr 2024Despite successful clinical management of castration-sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer is only...
PURPOSE
Despite successful clinical management of castration-sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer is only 32%. Combination treatment strategies to prevent disease recurrence are increasing, albeit in biomarker-unselected patients. Identifying a biomarker in CSPC to stratify patients who will progress on standard-of-care therapy could guide therapeutic strategies.
EXPERIMENTAL DESIGN
Targeted deep sequencing was performed for the University of Illinois (UI) cohort (n = 30), and immunostaining was performed on a patient tissue microarray (n = 149). Bioinformatic analyses identified pathways associated with biomarker overexpression (OE) in the UI cohort, consolidated RNA sequencing samples accessed from Database of Genotypes and Phenotypes (n = 664), and GSE209954 (n = 68). Neutralizing antibody patritumab and ectopic HER3 OE were utilized for functional mechanistic experiments.
RESULTS
We identified ERBB3 OE in diverse patient populations with CSPC, where it was associated with advanced disease at diagnosis. Bioinformatic analyses showed a positive correlation between ERBB3 expression and the androgen response pathway despite low dihydrotestosterone and stable expression of androgen receptor (AR) transcript in Black/African American men. At the protein level, HER3 expression was negatively correlated with intraprostatic androgen in Black/African American men. Mechanistically, HER3 promoted enzalutamide resistance in prostate cancer cell line models and HER3-targeted therapy resensitized therapy-resistant prostate cancer cell lines to enzalutamide.
CONCLUSIONS
In diverse patient populations with CSPC, ERBB3 OE was associated with high AR signaling despite low intraprostatic androgen. Mechanistic studies demonstrated a direct link between HER3 and enzalutamide resistance. ERBB3 OE as a biomarker could thus stratify patients for intensification of therapy in castration-sensitive disease, including targeting HER3 directly to improve sensitivity to AR-targeted therapies.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Androgens; Neoplasm Recurrence, Local; Receptors, Androgen; Nitriles; Biomarkers; Castration; Drug Resistance, Neoplasm; Cell Line, Tumor; Receptor, ErbB-3; Benzamides; Phenylthiohydantoin
PubMed: 38306015
DOI: 10.1158/1078-0432.CCR-23-2161 -
Frontiers in Endocrinology 2023Glucocorticoids are key executors of the physiological response to stress. Previous studies in mice showed that the androgen receptor (AR) influenced the transcriptional...
Glucocorticoids are key executors of the physiological response to stress. Previous studies in mice showed that the androgen receptor (AR) influenced the transcriptional outcome of glucocorticoid treatment in white and brown adipocytes and in the liver. In the brain, we observed that chronic hypercorticism induced changes in gene expression that tended to be more pronounced in male mice. In the present study, we investigated if glucocorticoid signaling in the brain could be modulated by androgen. After chronic treatment with corticosterone, dihydrotestosterone, a combination of both, and corticosterone in combination with the AR antagonist enzalutamide, we compared the expression of glucocorticoid receptor (NR3C1, also abbreviated GR) target genes in brain regions where AR and GR are co-expressed, namely: prefrontal cortex, hypothalamus, hippocampus, ventral tegmental area and substantia nigra. We observed that androgen affected glucocorticoid signaling only in the prefrontal cortex and the substantia nigra. Dihydrotestosterone and corticosterone independently and inversely regulated expression of and in prefrontal cortex. AR antagonism with enzalutamide attenuated corticosterone-induced expression of in the prefrontal cortex and of and in the substantia nigra. Additionally, in the substantia nigra, AR antagonism increased expression of and , two genes coding for key components of the dopaminergic system. Our data indicate that androgen influence over glucocorticoid stimulation in the brain is not a dominant phenomenon in the context of high corticosterone levels, but can occur in the prefrontal cortex and substantia nigra.
Topics: Male; Mice; Animals; Glucocorticoids; Androgens; Corticosterone; Dihydrotestosterone; Mesencephalon; Prefrontal Cortex; Benzamides; Nitriles; Phenylthiohydantoin
PubMed: 38303978
DOI: 10.3389/fendo.2023.1292024 -
Neuroscience Mar 2024Aggression is a social behavior that is critical for survival and reproduction. In adults, circulating gonadal hormones, such as androgens, act on neural circuits to...
Aggression is a social behavior that is critical for survival and reproduction. In adults, circulating gonadal hormones, such as androgens, act on neural circuits to modulate aggressive interactions, especially in reproductive contexts. In many species, individuals also demonstrate aggression before reaching gonadal maturation. Adult male song sparrows, Melospiza melodia, breed seasonally but maintain territories year-round. Juvenile (hatch-year) males aggressively compete for territory ownership during their first winter when circulating testosterone is low. Here, we characterized the relationship between the steroid milieu and aggressive behavior in free-living juvenile male song sparrows in winter. We investigated the effect of a 10 min simulated territorial intrusion (STI) on behavior and steroid levels in blood, 10 microdissected brain regions, and four peripheral tissues (liver, pectoral muscle, adrenal glands, and testes). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we quantified 12 steroids: pregnenolone, progesterone, corticosterone, 11-dehydrocorticosterone, dehydroepiandrosterone, androstenedione, testosterone, 5α-dihydrotestosterone, 17β-estradiol 17α-estradiol, estrone, and estriol. We found that juvenile males are robustly aggressive, like adult males. An STI increases progesterone and corticosterone levels in blood and brain and increases 11-dehydrocorticosterone levels in blood only. Pregnenolone, androgens, and estrogens are generally non-detectable and are not affected by an STI. In peripheral tissues, steroid concentrations are very high in the adrenals. These data suggest that adrenal steroids, such as progesterone and corticosterone, might promote juvenile aggression and that juvenile and adult songbirds might rely on distinct neuroendocrine mechanisms to support similar aggressive behaviors.
Topics: Humans; Animals; Male; Songbirds; Corticosterone; Progesterone; Chromatography, Liquid; Tandem Mass Spectrometry; Testosterone; Androgens; Aggression; Estradiol; Pregnenolone
PubMed: 38301739
DOI: 10.1016/j.neuroscience.2024.01.008 -
Science Signaling Jan 2024Androgen binding to the androgen receptor (AR) in the cytoplasm induces the AR to translocate to the nucleus, where it regulates the expression of target genes. Here, we...
Androgen binding to the androgen receptor (AR) in the cytoplasm induces the AR to translocate to the nucleus, where it regulates the expression of target genes. Here, we found that androgens rapidly activated a plasma membrane-associated signaling node that enhanced nuclear AR functions. In murine primary osteoblasts, dihydrotestosterone (DHT) binding to a membrane-associated form of AR stimulated plasma membrane-associated protein kinase G type 2 (PKG2), leading to the activation of multiple kinases, including ERK. Phosphorylation of AR at Ser by ERK increased the nuclear accumulation and binding of AR to the promoter of , which encodes the transcription factor β-catenin. In male mouse osteoblasts and human prostate cancer cells, DHT induced the expression of and , respectively, as well as β-catenin target genes, stimulating the proliferation, survival, and differentiation of osteoblasts and the proliferation of prostate cancer cells in a PKG2-dependent fashion. Because β-catenin is a master regulator of skeletal homeostasis, these results explain the reported male-specific osteoporotic phenotype of mice lacking PKG2 in osteoblasts and imply that PKG2-dependent AR signaling is essential for maintaining bone mass in vivo. Our results suggest that widely used pharmacological PKG activators, such as sildenafil, could be beneficial for male and estrogen-deficient female patients with osteoporosis but detrimental in patients with prostate cancer.
Topics: Animals; Humans; Male; Mice; Androgens; beta Catenin; Cell Line, Tumor; Cell Membrane; Dihydrotestosterone; Osteoblasts; Prostatic Neoplasms; Receptors, Androgen
PubMed: 38289986
DOI: 10.1126/scisignal.adi7861 -
Journal of Lipid Research Mar 2024Finasteride is commonly prescribed to treat benign prostate hyperplasia and male-pattern baldness in cis men and, more recently, trans individuals. However, the effect...
Finasteride is commonly prescribed to treat benign prostate hyperplasia and male-pattern baldness in cis men and, more recently, trans individuals. However, the effect of finasteride on cardiovascular disease remains elusive. We evaluated the role of finasteride on atherosclerosis using low-density lipoprotein (LDL) receptor-deficient (Ldlr) mice. Next, we examined the relevance to humans by analyzing the data deposited between 2009 and 2016 in the National Health and Nutrition Examination Survey. We show that finasteride reduces total plasma cholesterol and delays the development of atherosclerosis in Ldlr mice. Finasteride reduced monocytosis, monocyte recruitment to the lesion, macrophage lesion content, and necrotic core area, the latter of which is an indicator of plaque vulnerability in humans. RNA sequencing analysis revealed a downregulation of inflammatory pathways and an upregulation of bile acid metabolism, oxidative phosphorylation, and cholesterol pathways in the liver of mice taking finasteride. Men reporting the use of finasteride showed lower plasma levels of cholesterol and LDL-cholesterol than those not taking the drug. Our data unveil finasteride as a potential treatment to delay cardiovascular disease in people by improving the plasma lipid profile.
Topics: Humans; Male; Animals; Mice; Finasteride; Cardiovascular Diseases; Nutrition Surveys; Atherosclerosis; Cholesterol; Receptors, LDL; Mice, Knockout
PubMed: 38272355
DOI: 10.1016/j.jlr.2024.100507 -
Science Advances Jan 2024The brain-specific enzyme CYP46A1 controls cholesterol turnover by converting cholesterol into 24-hydroxycholesterol (24OH). Dysregulation of brain cholesterol turnover...
The brain-specific enzyme CYP46A1 controls cholesterol turnover by converting cholesterol into 24-hydroxycholesterol (24OH). Dysregulation of brain cholesterol turnover and reduced levels are observed in Alzheimer's disease (AD). In this study, we report that overexpression in aged female mice leads to enhanced estrogen signaling in the hippocampus and improved cognitive functions. In contrast, age-matched overexpressing males show anxiety-like behavior, worsened memory, and elevated levels of 5α-dihydrotestosterone in the hippocampus. We report that, in neurons, 24OH contributes to these divergent effects by activating sex hormone signaling, including estrogen receptors. overexpression in female mice protects from memory impairments induced by ovariectomy while having no effects in gonadectomized males. Last, we measured cerebrospinal fluid levels of 24OH in a clinical cohort of patients with AD and found that 24OH negatively correlates with neurodegeneration markers only in women. We suggest that CYP46A1 activation is a valuable pharmacological target for enhancing estrogen signaling in women at risk of developing neurodegenerative diseases.
Topics: Male; Female; Humans; Animals; Mice; Aged; Cholesterol 24-Hydroxylase; Memory Disorders; Cholesterol; Cognition; Alzheimer Disease; Estrogens
PubMed: 38266095
DOI: 10.1126/sciadv.adj1354 -
Biology of Sex Differences Jan 2024Androgens are important sex hormones in both men and women and are supplemented when endogenous levels are low, for gender transitioning, or to increase libido....
BACKGROUND
Androgens are important sex hormones in both men and women and are supplemented when endogenous levels are low, for gender transitioning, or to increase libido. Androgens also circulate at higher levels in women with polycystic ovarian syndrome, a condition that increases the risk for cardiovascular diseases including hypertension and arterial stiffness. Since our previous work shows an important role for the G protein-coupled estrogen receptor (GPER) in arterial stiffness, we hypothesized that other hormones including androgens may impact arterial stiffness in female mice via downregulation of GPER.
METHODS
The impact of the non-aromatizable androgen dihydrotestosterone (DHT), the glucocorticoid dexamethasone, and the progestin medroxyprogesterone acetate (all 100 nM for 24 h) on GPER and ERα expression was assessed in cultured vascular smooth muscle cells using droplet digital PCR (ddPCR). To assess the in vivo impact of the DHT-induced downregulation of GPER, female ovary-intact C57Bl/6 mice at 15-16 weeks of age were treated with silastic capsules containing DHT for 4 weeks, one with a dosage expected to mimic human male DHT levels and another to double the expected human concentration (n = 8-9/group).
RESULTS
In cultured vascular smooth muscle cells, GPER mRNA was decreased by DHT (P = 0.001) but was not impacted by dexamethasone or medroxyprogesterone. In contrast, ERα expression in cultured cells was significantly suppressed by all three hormones (P < 0.0001). In control mice or mice treated with a single or double dose of DHT, a dose-dependent increase in body weight was observed (control 22 ± 2 g, single dose 24 ± 2 g, double dose 26 ± 2 g; P = 0.0002). Intracarotid stiffness measured via pulse wave velocity showed a more than two-fold increase in both DHT-treated groups (control 1.9 ± 0.3 m/s, single dose 4.3 ± 0.8 m/s, double dose 4.8 ± 1.0 m/s). This increase in arterial stiffness occurred independent of changes in blood pressure (P = 0.59). Histological analysis of aortic sections using Masson's trichrome showed a significant decrease in collagen between the control group (24 ± 5%) and the double dose group (17 ± 3%, P = 0.007), despite no changes in aortic wall thickness or smooth muscle content. Lastly, ddPCR showed that in vivo DHT treatment decreased aortic expression of both GPER (control 20 ± 5, single dose 10.5 ± 5.6, double dose 10 ± 4 copies/ng; P = 0.001) and ERα (control 54 ± 2, single dose 24 ± 13, and double dose 23 ± 12 copies/ng; P = 0.003).
CONCLUSIONS
These findings indicate that androgen promotes arterial stiffening and cardiovascular damage in female mice and is associated with decreased estrogen receptor expression. These data are important for transgender men, women using testosterone for fitness or reduced libido, as well as patients with polycystic ovarian syndrome.
Topics: Female; Humans; Male; Animals; Mice; Infant, Newborn; Dihydrotestosterone; Androgens; Estrogen Receptor alpha; Polycystic Ovary Syndrome; Pulse Wave Analysis; Estrogens; Receptors, Estrogen; Dexamethasone
PubMed: 38263051
DOI: 10.1186/s13293-024-00586-3 -
Biomedicines Dec 2023Silver nanoparticles (AgNPs) are a popular engineered nanomaterial widely used in industry. Despite the benefits they bring to society, AgNPs are not neutral to human...
Silver nanoparticles (AgNPs) are a popular engineered nanomaterial widely used in industry. Despite the benefits they bring to society, AgNPs are not neutral to human health. The aim of this study was to evaluate the effects of a single intravenous dose (5 mg/kg body weight) of 20 nm AgNPs on steroid metabolism and redox balance in the testes of adult rats. The effects were evaluated 1 day or 28 days after intervention and compared with saline-treated animals. Decreased aromatase and estrogen receptor α levels (by 21% and 27%, respectively) were observed 1 day after AgNPs administration, while increased testosterone, increased dihydrotestosterone levels, higher androgen receptors and higher aromatase expression in Leydig cells (by 43%, 50%, 20% and 32%, respectively) as well as lower (by 35%) androgen receptor protein levels were observed 28 days after exposure to AgNPs compared to control groups. The AgNPs treatment resulted in decreased superoxide dismutase activity, decreased GSH/GSSG ratio, and increased glutathione reductase activity (by 23%, 63% and 28%, respectively) compared to control animals, irrespective of the time of measurement. Increased (by 28%) intratesticular lipid hydroperoxides level was observed 1 day after AgNPs exposure, while decreased (by 70%) GSH and increased (by 43%) 7-ketocholesterol levels were observed 28 days after treatment compared to control animals. Conclusions: AgNPs exposure caused redox imbalance in the gonads shortly after AgNPs administration, while a longer perspective AgNPs exposure was associated with impaired androgen metabolism, probably due to increased oxidative stress.
PubMed: 38255180
DOI: 10.3390/biomedicines12010073 -
Prostate International Dec 2023To evaluate the efficacy and safety of , Angelicae Gigantis Radix and Glycyrrhizae Radix complex (CAG) in men with moderate lower urinary tract symptoms (LUTS).
BACKGROUND
To evaluate the efficacy and safety of , Angelicae Gigantis Radix and Glycyrrhizae Radix complex (CAG) in men with moderate lower urinary tract symptoms (LUTS).
MATERIALS AND METHODS
From November 2020 to January 2022, participants with International Prostate Symptom Score (IPSS) of 12-19 in two centers were recruited and randomize into three groups: a CAG 500 mg/day group (CAG 500), a CAG 1000 mg/day group (CAG 1000), and a placebo group (PG). They were treated for 12 weeks. The primary endpoint was change of IPSS at the end of study from baseline. Secondary end points included change of prostate specific antigen (PSA), testosterone, dihydrotestosterone (DHT), maximum urinary flow rate (Q max), post-void residual volume (PVR), International Index of Erectile Function (IIEF), and drug safety.
RESULTS
A total of 103 patients were able to finish the study according to the study protocol. Total IPSS and sub-scores (residual urine sensation, frequency, weak stream, hesistancy, nocturia, and quality of life) in CAG 500 and CAG 1000 were significantly improved at the 12 week compared to those of the PG. Changes of serum PSA, DHT, and testosterone levels at the 12 week from baseline did not show significant differences among the three groups. Q max and PVR changes did not show significant differences among the three groups either. Total IIEF and sub-scores (erectile function, orgasmic function, sexual desire, intercourse satisfaction) in CAG 1000 were significantly improved at 12 week compared to those in PG. No significant adverse events were found.
CONCLUSIONS
CAG is well tolerated in patients with moderate LUTS. Treatment with CAG for 12 weeks has a therapeutic effect on moderate LUTS.
PubMed: 38196553
DOI: 10.1016/j.prnil.2023.09.002 -
BMC Women's Health Jan 2024Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphologic features, and PCOS is...
BACKGROUND
Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphologic features, and PCOS is associated with infertility. PH domain Leucine-rich repeat Protein Phosphatase 1 (PHLPP1) has been shown to regulate AKT. The aim of present study is to investigate the role of PHLPP1 in PCOS.
METHODS
The expression levels of PHLPP1 in dihydrotestosterone (DHT)-treated human ovarian granular KGN cells were determined by qRT-PCR and Western blot. PHLPP1 was silenced or overexpressed using lentivirus. Cell proliferation was detected by CCK-8. Apoptosis and ROS generation were analyzed by flow cytometry. Glycolysis was analyzed by measuring extracellular acidification rate (ECAR).
RESULTS
DHT treatment suppressed proliferation, promoted apoptosis, enhanced ROS, and inhibited glycolysis in KGN cells. PHLPP1 silencing alleviated the DHT-induced suppression of proliferation and glycolysis, and promotion of apoptosis and ROS in KGN cells. PHLPP1 regulated cell proliferation and glycolysis in human KGN cells via the AKT signaling pathway.
CONCLUSIONS
Our results showed that PHLPP1 mediates the proliferation and aerobic glycolysis activity of human ovarian granular cells through regulating AKT signaling.
Topics: Female; Humans; Polycystic Ovary Syndrome; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Glycolysis; Nuclear Proteins; Phosphoprotein Phosphatases
PubMed: 38184561
DOI: 10.1186/s12905-023-02872-5