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Seminars in Reproductive Medicine Jun 2024Anti-Müllerian hormone (AMH) is an important component within androgen receptor (AR)-regulated pathways governing the hyperandrogenic origin of polycystic ovary...
Anti-Müllerian hormone (AMH) is an important component within androgen receptor (AR)-regulated pathways governing the hyperandrogenic origin of polycystic ovary syndrome (PCOS). In women with PCOS, granulosa cell AMH overexpression in developing ovarian follicles contributes to elevated circulating AMH levels beginning at birth and continuing in adolescent daughters of PCOS women. A 6 to 7% incidence among PCOS women of gene variants coding for AMH or its receptor, AMHR2, suggests genetic contributions to AMH-related pathogenesis. Discrete gestational AMH administration to pregnant mice induces hypergonadotropic hyperandrogenic, PCOS-like female offspring with high circulating AMH levels that persist over three generations, suggesting epigenetic contributions to PCOS through developmental programming. Moreover, adult-onset, selective hyperactivation of hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH) induces hypergonadotropic hyperandrogenism and PCOS-like traits in female mice. Both gestational and adult AMH inductions of PCOS-like traits are prevented by GnRH antagonist coadministration, implicating luteinizing hormone-dependent ovarian theca cell testosterone (T) action, mediated through the AR in AMH-induced pathogenesis. Interestingly, gestational or peripubertal exogenous T or dihydrotestosterone induction of PCOS-like traits in female mice, rats, sheep, and monkeys fails to elicit ovarian AMH hypersecretion; thus, AMH excess per se may lead to a distinct pathogenic contribution to hyperandrogenic PCOS origins.
PubMed: 38908381
DOI: 10.1055/s-0044-1787525 -
Critical Reviews in Oncology/hematology Jun 2024Genitourinary cancers (GUCs) encompass malignancies affecting the urinary and reproductive systems, including renal cell carcinoma (RCC), urothelial carcinoma (UC), and... (Review)
Review
CONTEXT
Genitourinary cancers (GUCs) encompass malignancies affecting the urinary and reproductive systems, including renal cell carcinoma (RCC), urothelial carcinoma (UC), and prostate cancer (PC). With the rapidly evolving therapeutic domain of these cancers, cutaneous adverse events (AEs) remain among the most observed toxicities.
OBJECTIVE
To explore the dermatologic AEs linked to novel GUC treatments, their underlying pathophysiology, clinical presentations, and risk factors.
EVIDENCE ACQUISITION
A narrative review of the literature from PubMed and Embase databases was conducted. The search strategy included dermatologic/cutaneous adverse events, risk factors, and pathophysiology in conjunction with the following classes of therapies; immune checkpoint inhibitors (ICIs), antiangiogenic therapies, enfortumab vedotin (EV), erdafitinib, and androgen receptor antagonists (ARAs).
EVIDENCE SYNTHESIS
Maculopapular rash, pruritus, and alopecia are present among the five classes of therapies. ICIs demonstrate the highest incidence of severe drug AEs including Steven Johnson syndrome/toxic epidermal necrolysis. Unique cutaneous AEs present with specific therapies including hand-foot skin reaction and subungual splinter hemorrhage with antiangiogenic drugs, stomatitis/mucositis and onycholysis with erdafitinib. Incidence and type of cutaneous AE also differed within therapies in the same class as seen with apalutamide displaying the highest risk of cutaneous AEs within ARAs. Risk factors for development of cutaneous AEs can be general to therapies, or specific, and include age, immune status, BMI, and gender.
CONCLUSIONS
Dermatologic AEs may impact patients' quality of life and increase the tendency to dose reduce, hold or discontinue life-saving therapies, underscoring the need for vigilant monitoring, early recognition, and collaborative management between medical oncologists, pharmacists, dermatologists and other specialists.
PubMed: 38906514
DOI: 10.1016/j.critrevonc.2024.104420 -
Chemosphere Jun 2024The water accommodated fraction (WAF) of spilled crude oil is a severe threat to the health of marine fish. This study was conducted to investigate the effects of...
The water accommodated fraction (WAF) of spilled crude oil is a severe threat to the health of marine fish. This study was conducted to investigate the effects of short-term embryonic exposure to the WAF on the ovarian development and reproductive capability of F0 adult female marine medaka (Oryzias melastigma). Following embryonic exposure to the WAF with nominal total petroleum hydrocarbon concentrations of 0.5, 5, 50, and 500 μg/L for 7 days, the number of spawned eggs and gonadosomatic indices of F0 adult females were significantly reduced at 130 days postfertilization. In these F0 adult females, the proportion of mature oocytes was significantly lower, the level of 17β-estradiol was lower, and the level of testosterone was greater than those in control group. The mRNA levels of the follicle-stimulating hormone β subunit, luteinizing hormone β subunit, cytochrome P450 aromatase 19b, estrogen receptor α and β, and androgen receptor α and β genes were upregulated, while the mRNA level of the salmon-type gonadotropin-releasing hormone was downregulated in F0 adult females exposed to the WAF during the embryonic stage. Additionally, the methylation level of vitellogenin (vtg) in F0 adult females was significantly elevated, this might have, in turn, downregulated the mRNA level of vtg. The mortality rate of the unexposed F1 embryos was significantly increased and the hatching success was significantly reduced. These results collectively indicated the necessity of incorporating and evaluating the effects of short-term early-life exposure to crude oil in the assessment of risks to the reproductive health of marine fish.
PubMed: 38906194
DOI: 10.1016/j.chemosphere.2024.142616 -
JCO Precision Oncology Jun 2024Androgen receptor splice variant 7 (ARV-7) is a resistance mechanism to hormonal therapy in metastatic castrate-resistant prostate cancer (mCRPC). It has been associated...
PURPOSE
Androgen receptor splice variant 7 (ARV-7) is a resistance mechanism to hormonal therapy in metastatic castrate-resistant prostate cancer (mCRPC). It has been associated with poor outcomes. On progression to castrate resistance, ARV-7 positivity has been identified in global populations at an incidence of 17.8%-28.8%. Here, we characterize the incidence of ARV-7 positivity in Asian patients with mCRPC in a prospective fashion and evaluate its implications on treatment outcomes.
METHODS
Patients with mCRPC from multiple centers in Southeast and East Asia were enrolled in a prospective manner before initiation of androgen receptor signaling inhibitors or docetaxel. ARV-7 status was evaluated at baseline with three commercially available assays: AdnaTest Prostate Cancer platform, Clearbridge method, and IBN method. Clinical outcomes at progression were assessed. The primary end point of this study was prevalence of ARV-7 positivity; secondary end points were incidence of ARV-7 positivity, prostate specific antigen (PSA) response rate, PSA progression-free survival (PFS), and overall survival (OS).
RESULTS
A total of 102 patients with a median age of 72 years at enrollment participated. Overall, an incidence of ARV-7 positivity of between 14.3% and 33.7% in Asian patients with mCRPC was demonstrated depending on the assay used. Patients found to have ARV-7 positivity at enrollment had a numerically worse PSA PFS compared with ARV-7 negative patients.
CONCLUSION
In this study, the incidence of ARV-7 positivity in Asian patients with mCRPC was shown to be similar to the global population. Patients with ARV-7 positivity appear to have more aggressive disease with numerically worse PSA PFS and OS. Further prospective studies are needed to fully characterize the relationship that ARV-7 positivity has on prognosis of Asian patients with mCRPC.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Aged; Receptors, Androgen; Middle Aged; Prospective Studies; Aged, 80 and over; Asian People; Neoplasm Metastasis; Protein Isoforms
PubMed: 38905583
DOI: 10.1200/PO.23.00694 -
The Tokai Journal of Experimental and... Jul 2024Recently, effectiveness of local treatment for oncological outcomes for patients with metastatic prostate cancer (PC) has been reported. We performed hemi-ablation with...
Recently, effectiveness of local treatment for oncological outcomes for patients with metastatic prostate cancer (PC) has been reported. We performed hemi-ablation with high-intensity focused ultrasound (HIFU) for a patient with a localized reducted solitary lesion in the prostate, which was diagnosed with magnetic resonance imaging (MRI)-transrectal ultrasound fusion image-guided target biopsy with PSA level of 0.24 ng/mL, after androgen receptor signaling inhibitors (ARSIs) and chemotherapy for metastatic PC. Prostate specific antigen levels decreased to 0.01ng/mL at 1 month after the treatment, and cancer suspicious lesion disappeared on MRI. During the follow-up of 24 months, there was no elevation of PSA level with no severe complication related to the treatment. HIFU has possibility to be an effective and minimally invasive treatment as a local treatment for the localized reducted solitary lesion in the prostate after ARSIs and chemotherapy for metastatic PC.
Topics: Humans; Male; Prostatic Neoplasms; Treatment Outcome; Prostate-Specific Antigen; Magnetic Resonance Imaging; Aged; High-Intensity Focused Ultrasound Ablation; Image-Guided Biopsy; Androgen Receptor Antagonists; Prostate
PubMed: 38904239
DOI: No ID Found -
Journal of Experimental & Clinical... Jun 2024The androgen receptor (AR) is a drug target used to inhibit AR and prostate cancer (PCa) growth. Surprisingly, treatment with supraphysiological androgen level (SAL),...
BACKGROUND
The androgen receptor (AR) is a drug target used to inhibit AR and prostate cancer (PCa) growth. Surprisingly, treatment with supraphysiological androgen level (SAL), used in bipolar androgen therapy, inhibits growth of PCa suggesting a tumor-suppressive activity by SAL. SAL was shown to induce cellular senescence in PCa.
METHODS
RNA-seq and transcriptome analysis, ChIP-seq, human 3D PCa spheroids, mouse xenografted castration-resistant PCa, knockdown and overexpression, Co-immunoprecipitation (Co-IP), translocation analysis, immune detection, qRT-PCR, protein-protein interaction modelling.
RESULTS
Here, mice xenografts with castration-resistant PCa tumors show that SAL inhibits cancer growth in vivo suggesting that SAL activates a tumor-suppressive mechanism. RNA-seq and ChIP-seq revealed the clock gene BHLHE40 is a novel direct AR target. Compared to adjacent human prostate tissues, the expression of BHLHE40 is reduced in PCa tumors and associated with reduced survival. Knockdown suggests that BHLHE40 mediates SAL-induced cellular senescence including tumor spheroids. Interestingly, a large overlap of differentially expressed gene sets was identified between BHLHE40 and SAL leading to the identification of four classes of SAL-BHLHE40 transcriptome landscapes. Co-IP and modelling suggest binding of BHLHE40 to AR and their co-translocation into nucleus by SAL treatment. Further, RNA-seq and ChIP-seq analysis indicate that the atypical tumor suppressive cyclin G2 emerged as a novel downstream target of BHLHE40 and a mediator of SAL-induced cellular senescence.
CONCLUSIONS
The data provide evidence of the tumor suppressive activity of SAL and a novel signaling by the AR-BHLHE40-CCNG2 axis for androgen-induced cellular senescence, linking circadian rhythm factor to androgen signaling as a novel tumor suppressive pathway.
Topics: Male; Humans; Cellular Senescence; Mice; Animals; Prostatic Neoplasms; Basic Helix-Loop-Helix Transcription Factors; Androgens; Cell Line, Tumor; Homeodomain Proteins; Receptors, Androgen; Gene Expression Regulation, Neoplastic; Xenograft Model Antitumor Assays
PubMed: 38902772
DOI: 10.1186/s13046-024-03097-6 -
Cell Death and Differentiation Jun 2024The dynamic crosstalk between tumor and stromal cells is a major determinant of cancer aggressiveness. The tumor-suppressor DAB2IP (Disabled homolog 2 interacting... (Review)
Review
The dynamic crosstalk between tumor and stromal cells is a major determinant of cancer aggressiveness. The tumor-suppressor DAB2IP (Disabled homolog 2 interacting protein) plays an important role in this context, since it modulates cell responses to multiple extracellular inputs, including inflammatory cytokines and growth factors. DAB2IP is a RasGAP and negatively controls Ras-dependent mitogenic signals. In addition, it modulates other major oncogenic pathways, including TNFα/NF-κB, WNT/β-catenin, PI3K/AKT, and androgen receptor signaling. In line with its tumor-suppressive role, DAB2IP is frequently inactivated in cancer by transcriptional and post-transcriptional mechanisms, including promoter methylation, microRNA-mediated downregulation, and protein-protein interactions. Intriguingly, some observations suggest that downregulation of DAB2IP in cells of the tumor stroma could foster establishment of a pro-metastatic microenvironment. This review summarizes recent insights into the tumor-suppressive functions of DAB2IP and the consequences of its inactivation in cancer. In particular, we explore potential approaches aimed at reactivating DAB2IP, or augmenting its expression levels, as a novel strategy in cancer treatment. We suggest that reactivation or upregulation of DAB2IP would concurrently attenuate multiple oncogenic pathways in both cancer cells and the tumor microenvironment, with implications for improved treatment of a broad spectrum of tumors.
PubMed: 38902547
DOI: 10.1038/s41418-024-01332-3 -
Environmental Pollution (Barking, Essex... Jun 2024Biomonitoring studies have shown that pregnant women living in regions of unconventional natural gas (UNG) exploitation have higher levels of trace elements. Whether...
Biomonitoring studies have shown that pregnant women living in regions of unconventional natural gas (UNG) exploitation have higher levels of trace elements. Whether developmental endocrine disruption can be expected at these exposure levels during pregnancy is unclear. In this study, we aimed to test the impact of five trace elements alone or in mixtures using in vitro cell- and tissue-based assays relevant to endocrine disruption and development. Manganese, aluminum, strontium, barium, and cobalt were tested at concentrations including those representatives of human fetal exposure. Using transactivation assays, none of the tested elements nor their mixture altered the human estrogen receptor 1 or androgen receptor genomic signalling. In the rat fetal testis assay, an organ culture system, cobalt (5 μg/l), barium (500 μg/l) and strontium (500 μg/l) significantly increased testosterone secretion. Cobalt and strontium were associated with hyperplasia and/or hypertrophy of fetal Leydig cells. Mixing the five elements at concentrations where none had an effect individually stimulated testosterone secretion by the rat fetal testis paralleled by the significant increase of 3β-hydroxysteroid dehydrogenase protein level in comparison to the vehicle control. The mechanisms involved may be specific to the fetal testis as no effect was observed in the steroidogenic H295R cells. Our data suggest that some trace elements in mixture at concentrations representative of human fetal exposure can impact testis development and function. This study highlights the potential risk posed by UNG operations, especially for the most vulnerable populations, pregnant individuals, and their fetus.
PubMed: 38901820
DOI: 10.1016/j.envpol.2024.124393 -
The Journal of Clinical Investigation Jun 2024Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease...
Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease with a higher prevalence and fatality rate in men than women. However, the mechanism by which androgen mediates aortic aneurysms is largely unknown. Herein, we found that male mice, not female mice, developed aortic aneurysms when exposed to aldosterone and high salt (Aldo-salt). We revealed that androgen and androgen receptors (AR) were crucial for this sexually dimorphic response to Aldo-salt. We identified programmed cell death protein 1 (PD-1), an immune checkpoint, as a key link between androgen and aortic aneurysms. We demonstrated that administration of anti-PD-1 Ab and adoptive PD-1 deficient T cell transfer reinstated Aldo-salt-induced aortic aneurysms in orchiectomized mice, and genetic deletion of PD-1 exacerbated aortic aneurysms induced by high-fat diet and angiotensin II (Ang II) in non-orchiectomized mice. Mechanistically, we discovered that AR bound to the PD-1 promoter to suppress its expression in the spleen. Thus, our study unveils a mechanism by which androgen aggravates aortic aneurysms by suppressing PD-1 expression in T cells. Moreover, our study suggests that some cancer patients might benefit from screenings for aortic aneurysms during immune checkpoint therapy.
PubMed: 38900572
DOI: 10.1172/JCI169085 -
Cell Communication and Signaling : CCS Jun 2024Endocrine resistance driven by sustained activation of androgen receptor (AR) signaling pathway in advanced prostate cancer (PCa) is fatal. Characterization of...
BACKGROUND
Endocrine resistance driven by sustained activation of androgen receptor (AR) signaling pathway in advanced prostate cancer (PCa) is fatal. Characterization of mechanisms underlying aberrant AR pathway activation to search for potential therapeutic strategy is particularly important. Rac GTPase-activating protein 1 (RACGAP1) is one of the specific GTPase-activating proteins. As a novel tumor proto-oncogene, overexpression of RACGAP1 was related to the occurrence of various tumors.
METHODS
Bioinformatics methods were used to analyze the relationship of expression level between RACGAP1 and AR as well as AR pathway activation. qRT-PCR and western blotting assays were performed to assess the expression of AR/AR-V7 and RACGAP1 in PCa cells. Immunoprecipitation and immunofluorescence experiments were conducted to detect the interaction and co-localization between RACGAP1 and AR/AR-V7. Gain- and loss-of-function analyses were conducted to investigate the biological roles of RACGAP1 in PCa cells, using MTS and colony formation assays. In vivo experiments were conducted to evaluate the effect of RACGAP1 inhibition on the tumor growth.
RESULTS
RACGAP1 was a gene activated by AR, which was markedly upregulated in PCa patients with CRPC and enzalutamide resistance. AR transcriptionally activated RACGAP1 expression by binding to its promoter region. Reciprocally, nuclear RACGAP1 bound to the N-terminal domain (NTD) of both AR and AR-V7, blocking their interaction with the E3 ubiquitin ligase MDM2. Consequently, this prevented the degradation of AR/AR-V7 in a ubiquitin-proteasome-dependent pathway. Notably, the positive feedback loop between RACGAP1 and AR/AR-V7 contributed to endocrine therapy resistance of CRPC. Combination of enzalutamide and in vivo cholesterol-conjugated RIG-I siRNA drugs targeting RACGAP1 induced potent inhibition of xenograft tumor growth of PCa.
CONCLUSION
In summary, our results reveal that reciprocal regulation between RACGAP1 and AR/AR-V7 contributes to the endocrine resistance in PCa. These findings highlight the therapeutic potential of combined RACGAP1 inhibition and enzalutamide in treatment of advanced PCa.
Topics: Male; Humans; Drug Resistance, Neoplasm; Receptors, Androgen; GTPase-Activating Proteins; Prostatic Neoplasms; Cell Line, Tumor; Animals; Proto-Oncogene Mas; Gene Expression Regulation, Neoplastic; Phenylthiohydantoin; Mice, Nude; Nitriles; Mice; Benzamides; Cell Proliferation; Proto-Oncogene Proteins c-mdm2; Signal Transduction
PubMed: 38898473
DOI: 10.1186/s12964-024-01703-w