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1
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Vrzalova A, Vrzal R. Orchestra of ligand-activated transcription factors in the molecular symphony of SERPINE 1 / PAI-1 gene regulation. Biochimie 2025; 228:138-157. [PMID: 39321911 DOI: 10.1016/j.biochi.2024.09.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 09/04/2024] [Accepted: 09/20/2024] [Indexed: 09/27/2024]
Abstract
Plasminogen activator inhibitor 1 (PAI-1) is a crucial serine protease inhibitor that prevents plasminogen activation by inhibiting tissue- and urokinase-type plasminogen activators (tPA, uPA). PAI-1 is well-known for its role in modulating hemocoagulation or extracellular matrix formation by inhibiting plasmin or matrix metalloproteinases, respectively. PAI-1 is induced by pro-inflammatory cytokines across various tissues, yet its regulation by ligand-activated transcription factors is partly disregarded. Therefore, we have attempted to summarize the current knowledge on the transcriptional regulation of PAI-1 expression by the most relevant xenobiotic and endocrine receptors implicated in modulating PAI-1 levels. This review aims to contribute to the understanding of the specific, often tissue-dependent regulation of PAI-1 and provide insights into the modulation of PAI-1 levels beyond its direct inhibition.
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Affiliation(s)
- Aneta Vrzalova
- Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic
| | - Radim Vrzal
- Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic.
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2
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van der Heijden LT, Ribbers CA, Vermunt MAC, Pluim D, Acda M, Tibben M, Rosing H, Douma JAJ, Naipal K, Bergman AM, Beijnen JH, Huitema ADR, Opdam FL. Is Higher Docetaxel Clearance in Prostate Cancer Patients Explained by Higher CYP3A? An In Vivo Phenotyping Study with Midazolam. J Clin Pharmacol 2024; 64:155-163. [PMID: 37789682 DOI: 10.1002/jcph.2362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 09/29/2023] [Indexed: 10/05/2023]
Abstract
Patients with prostate cancer (PCa) have a lower docetaxel exposure for both intravenous (1.8-fold) and oral administration (2.4-fold) than patients with other solid cancers, which could influence efficacy and toxicity. An altered metabolism by cytochrome P450 3A (CYP3A) due to castration status might explain the observed difference in docetaxel pharmacokinetics. In this in vivo phenotyping, pharmacokinetic study, CYP3A activity defined by midazolam clearance (CL) was compared between patients with PCa and male patients with other solid tumors. All patients with solid tumors who did not use CYP3A-modulating drugs were eligible for participation. Patients received 2 mg midazolam orally and 1 mg midazolam intravenously on 2 consecutive days. Plasma concentrations were measured with a validated liquid chromatography-tandem mass spectrometry method. Genotyping was performed for CYP3A4 and CYP3A5. Nine patients were included in each group. Oral midazolam CL was 1.26-fold higher in patients with PCa compared to patients with other solid tumors (geometric mean [coefficient of variation], 94.1 [33.5%] L/h vs 74.4 [39.1%] L/h, respectively; P = .08). Intravenous midazolam CL did not significantly differ between the 2 groups (P = .93). Moreover, the metabolic ratio of midazolam to 1'-hydroxy midazolam did not differ between the 2 groups for both oral administration (P = .67) and intravenous administration (P = .26). CYP3A4 and CYP3A5 genotypes did not influence midazolam pharmacokinetics. The observed difference in docetaxel pharmacokinetics between both patient groups therefore appears to be explained neither by a difference in midazolam CL nor by a difference in metabolic conversion rate of midazolam.
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Affiliation(s)
- Lisa T van der Heijden
- Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Division of Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Claire A Ribbers
- Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Division of Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Marit A C Vermunt
- Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Division of Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Dick Pluim
- Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Division of Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Manon Acda
- Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Division of Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Matthijs Tibben
- Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Division of Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Hilde Rosing
- Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Division of Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Joeri A J Douma
- Department of Clinical Pharmacology, Division of Medical Oncology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, The Netherlands
- Department of Internal Medicine, Medisch Centrum Leeuwarden, Leeuwarden, The Netherlands
| | - Kishan Naipal
- Department of Clinical Pharmacology, Division of Medical Oncology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, The Netherlands
| | - Andre M Bergman
- Department of Clinical Pharmacology, Division of Medical Oncology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, The Netherlands
- Department of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jos H Beijnen
- Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Division of Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Division of Pharmaco-epidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Alwin D R Huitema
- Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Division of Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Clinical Pharmacy, University Medical Center Utrecht Utrecht University, Utrecht, The Netherlands
- Department of Pharmacology, Princess Maxima Center, Utrecht, The Netherlands
| | - Frans L Opdam
- Department of Clinical Pharmacology, Division of Medical Oncology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute, The Netherlands
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Chong ZX, Yong CY, Ong AHK, Yeap SK, Ho WY. Deciphering the roles of aryl hydrocarbon receptor (AHR) in regulating carcinogenesis. Toxicology 2023; 495:153596. [PMID: 37480978 DOI: 10.1016/j.tox.2023.153596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/13/2023] [Accepted: 07/16/2023] [Indexed: 07/24/2023]
Abstract
Aryl hydrocarbon receptor (AHR) is a ligand-dependent receptor that belongs to the superfamily of basic helix-loop-helix (bHLH) transcription factors. The activation of the canonical AHR signaling pathway is known to induce the expression of cytochrome P450 enzymes, facilitating the detoxification metabolism in the human body. Additionally, AHR could interact with various signaling pathways such as epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), hypoxia-inducible factor-1α (HIF-1α), nuclear factor ekappa B (NF-κβ), estrogen receptor (ER), and androgen receptor (AR) signaling pathways. Over the past 30 years, several studies have reported that various chemical, physical, or biological agents, such as tobacco, hydrocarbon compounds, industrial and agricultural chemical wastes, drugs, UV, viruses, and other toxins, could affect AHR expression or activity, promoting cancer development. Thus, it is valuable to overview how these factors regulate AHR-mediated carcinogenesis. Current findings have reported that many compounds could act as AHR ligands to drive the expressions of AHR-target genes, such as CYP1A1, CYP1B1, MMPs, and AXL, and other targets that exert a pro-proliferation or anti-apoptotic effect, like XIAP. Furthermore, some other physical and chemical agents, such as UV and 3-methylcholanthrene, could promote AHR signaling activities, increasing the signaling activities of a few oncogenic pathways, such as the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways. Understanding how various factors regulate AHR-mediated carcinogenesis processes helps clinicians and scientists plan personalized therapeutic strategies to improve anti-cancer treatment efficacy. As many studies that have reported the roles of AHR in regulating carcinogenesis are preclinical or observational clinical studies that did not explore the detailed mechanisms of how different chemical, physical, or biological agents promote AHR-mediated carcinogenesis processes, future studies should focus on conducting large-scale and functional studies to unravel the underlying mechanism of how AHR interacts with different factors in regulating carcinogenesis processes.
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Affiliation(s)
- Zhi Xiong Chong
- Faculty of Science and Engineering, University of Nottingham Malaysia, 43500 Semenyih, Selangor, Malaysia
| | - Chean Yeah Yong
- China-ASEAN College of Marine Sciences, Xiamen University Malaysia, 43900 Sepang, Selangor, Malaysia
| | - Alan Han Kiat Ong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, 43000 Kajang, Malaysia
| | - Swee Keong Yeap
- China-ASEAN College of Marine Sciences, Xiamen University Malaysia, 43900 Sepang, Selangor, Malaysia.
| | - Wan Yong Ho
- Faculty of Science and Engineering, University of Nottingham Malaysia, 43500 Semenyih, Selangor, Malaysia.
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Bensreti H, Yu K, Alhamad DW, Shaver J, Kaiser H, Zhong R, Whichard WC, Parker E, Grater L, Faith H, Johnson M, Cooley MA, Fulzele S, Hill WD, Isales CM, Hamrick MW, McGee-Lawrence ME. Orchiectomy sensitizes cortical bone in male mice to the harmful effects of kynurenine. Bone 2023; 173:116811. [PMID: 37244427 PMCID: PMC10330684 DOI: 10.1016/j.bone.2023.116811] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/17/2023] [Accepted: 05/19/2023] [Indexed: 05/29/2023]
Abstract
Kynurenine (Kyn) is a tryptophan metabolite that increases with age and promotes musculoskeletal dysfunction. We previously found a sexually dimorphic pattern in how Kyn affects bone, with harmful effects more prevalent in females than males. This raises the possibility that male sex steroids might exert a protective effect that blunts the effects of Kyn in males. To test this, orchiectomy (ORX) or sham surgeries were performed on 6-month-old C57BL/6 mice, after which mice received Kyn (10 mg/kg) or vehicle via intraperitoneal injection, once daily, 5×/week, for four weeks. Bone histomorphometry, DXA, microCT, and serum marker analyses were performed after sacrifice. In vitro studies were performed to specifically test the effect of testosterone on activation of aryl hydrocarbon receptor (AhR)-mediated signaling by Kyn in mesenchymal-lineage cells. Kyn treatment reduced cortical bone mass in ORX- but not sham-operated mice. Trabecular bone was unaffected. Kyn's effects on cortical bone in ORX mice were attributed primarily to enhanced endosteal bone resorption activity. Bone marrow adipose tissue was increased in Kyn-treated ORX animals but was unchanged by Kyn in sham-operated mice. ORX surgery increased mRNA expression of the aryl hydrocarbon receptor (AhR) and its target gene Cyp1a1 in the bone, suggesting a priming and/or amplification of AhR signaling pathways. Mechanistic in vitro studies revealed that testosterone blunted Kyn-stimulated AhR transcriptional activity and Cyp1a1 expression in mesenchymal-linage cells. These data suggest a protective role for male sex steroids in blunting the harmful effects of Kyn in cortical bone. Therefore, testosterone may play an important role in regulating Kyn/AhR signaling in musculoskeletal tissues, suggesting crosstalk between male sex steroids and Kyn signaling may influence age-associated musculoskeletal frailty.
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Affiliation(s)
- Husam Bensreti
- Department of Cellular Biology and Anatomy, Medical College of, Georgia at Augusta University, Augusta, GA, United States of America
| | - Kanglun Yu
- Department of Cellular Biology and Anatomy, Medical College of, Georgia at Augusta University, Augusta, GA, United States of America
| | - Dima W Alhamad
- Department of Cellular Biology and Anatomy, Medical College of, Georgia at Augusta University, Augusta, GA, United States of America
| | - Joseph Shaver
- Department of Cellular Biology and Anatomy, Medical College of, Georgia at Augusta University, Augusta, GA, United States of America
| | - Helen Kaiser
- Biomedical Sciences, University of South Carolina School of Medicine Greenville, Greenville, SC, United States of America
| | - Roger Zhong
- Department of Neuroscience & Regenerative Medicine, Medical College of, Georgia at Augusta University, Augusta, GA, United States of America
| | - William C Whichard
- Department of Cellular Biology and Anatomy, Medical College of, Georgia at Augusta University, Augusta, GA, United States of America
| | - Emily Parker
- Department of Cellular Biology and Anatomy, Medical College of, Georgia at Augusta University, Augusta, GA, United States of America
| | - Lindsey Grater
- Department of Cellular Biology and Anatomy, Medical College of, Georgia at Augusta University, Augusta, GA, United States of America
| | - Hayden Faith
- Department of Cellular Biology and Anatomy, Medical College of, Georgia at Augusta University, Augusta, GA, United States of America
| | - Maribeth Johnson
- Department of Neuroscience & Regenerative Medicine, Medical College of, Georgia at Augusta University, Augusta, GA, United States of America
| | - Marion A Cooley
- Department of Oral Biology & Diagnostic Sciences, Dental Collage of Georgia at Augusta University, Augusta, GA, United States of America
| | - Sadanand Fulzele
- Department of Cellular Biology and Anatomy, Medical College of, Georgia at Augusta University, Augusta, GA, United States of America
| | - William D Hill
- Department of Pathology, Medical University of South Carolina, Charleston, SC, United States of America
| | - Carlos M Isales
- Department of Neuroscience & Regenerative Medicine, Medical College of, Georgia at Augusta University, Augusta, GA, United States of America
| | - Mark W Hamrick
- Department of Cellular Biology and Anatomy, Medical College of, Georgia at Augusta University, Augusta, GA, United States of America
| | - Meghan E McGee-Lawrence
- Department of Cellular Biology and Anatomy, Medical College of, Georgia at Augusta University, Augusta, GA, United States of America.
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Convissar S, Bennett-Toomey J, Stocco C. Insulin-like growth factor 1 enhances follicle-stimulating hormone-induced phosphorylation of GATA4 in rat granulosa cells. Mol Cell Endocrinol 2023; 559:111807. [PMID: 36279967 PMCID: PMC10041677 DOI: 10.1016/j.mce.2022.111807] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/05/2022] [Accepted: 10/17/2022] [Indexed: 11/06/2022]
Abstract
Preovulatory granulosa cell (GC) differentiation is essential for the maturation and release of oocytes from the ovary. We have previously demonstrated that follicle-stimulating hormone (FSH) and insulin-like growth factors (IGFs) closely interact to control GC function. Similarly, we showed that GATA4 mediates FSH actions and it is required for preovulatory follicle formation. This report aimed to determine in vivo the effect of FSH on GATA4 phosphorylation and to investigate whether FSH and IGF1 interact to regulate GATA4 activity. In rat ovaries, treatment with equine chorionic gonadotropin (eCG) increased the phosphorylation of GATA4, which was confined to the nucleus of GCs. Using primary rat GCs, we observed that GATA4 phosphorylation at serine 105 increases the transcriptional activity of this transcription factor. Like FSH, IGF1 stimulated GATA4 phosphorylation at serine 105. Interestingly, GATA4 phosphorylation was significantly higher in cells cotreated with FSH and IGF1 when compared to FSH or IGF1 alone, suggesting that IGF1 augments the effects of FSH on GATA4. It was also found that the enhancing effect of IGF1 requires AKT activity and is mimicked by the inhibition of glycogen synthase kinase-3 β (GSK3β), suggesting that AKT inhibition of GSK3β may play a role in the regulation of GATA4 phosphorylation. The data support an important role of the IGF1/AKT/GSK3β signaling pathway in the regulation of GATA4 transcriptional activity and provide new insights into the mechanisms by which FSH and IGF1 regulate GC differentiation. Our findings suggest that GATA4 transcriptional activation may, at least partially, mediate AKT actions in GCs.
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Affiliation(s)
- Scott Convissar
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Jill Bennett-Toomey
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Carlos Stocco
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA.
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Ren H, Tang Q, Xue T, Wang Q, Xu H, Zhang Q, Pan C. A 24-bp indel within the sheep AHR gene is associated with litter size. Anim Biotechnol 2022; 33:1533-1538. [PMID: 33947312 DOI: 10.1080/10495398.2021.1914071] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Aryl Hydrocarbon Receptor (AHR) is a member of the PER-ARNT-SIM (PAS) family, which could mediate various biological processes, for instance, the balance of the immune system, cell proliferation, differentiation, vascular tissue remodeling and reproduction ability regulation. A previous research showed that the AHR gene exerted important functions on the pig reproduction, implying that it could serve as a candidate gene related to animal reproductive traits. Here, the aim of this work was to identify potential insertion/deletion (indel) mutations of the AHR gene in three sheep breeds and analyze the associations between these mutations and reproductive traits. Results showed that a 24-bp indel was uncovered three genotypes (II, ID and DD) in the Australian White sheep (AuW) and Lanzhou fat-tail sheep (LZFT) population, while there were only two genotypes (ID and DD) in Luxi black-headed sheep (LXBH). Moreover, the Fisher's exact test showed that the 24-bp indel mutation was significantly associated with litter size and live litter size in AuW sheep (Fisher's p < 0.05). Therefore, the 24-bp indel of sheep AHR gene can contribute to sheep marker-assisted selection breeding and further improve the sheep reproductive performance.
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Affiliation(s)
- Hongying Ren
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Qi Tang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Tao Xue
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Qian Wang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Hongwei Xu
- College of Life Science and Engineering, Northwest Minzu University, Lanzhou, China.,Gansu Tech Innovation Center of Animal Cell, Biomedical Research Center, Northwest Minzu University, Lanzhou, China
| | - Qingfeng Zhang
- Tianjin Aoqun Sheep Industry Academy Company, Tianjin, China.,Tianjin Aoqun Animal Husbandry co., Ltd, Tianjin, China
| | - Chuanying Pan
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
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Eini F, kutenaei MA, Foroutan T, Salehi E. High levels of follicular fluid testosterone could impair oocyte developmental competency via affecting aryl hydrocarbon receptor pathway in PCOS patients. BMC Mol Cell Biol 2022; 23:47. [DOI: 10.1186/s12860-022-00449-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 11/04/2022] [Indexed: 11/13/2022] Open
Abstract
Abstract
Background
Although hormonal and metabolic dysfunction have been recognized as a possible cause of polycystic ovarian syndrome (PCOS), the associations between hyperandrogenism and aryl hydrocarbon receptor (Ahr) signaling pathway remains controversial. The current study aimed to investigate the effect of hyperandrogenism on oocyte developmental competency via regarding Ahr signaling downstream pathway in granulosa cells.
Materials and methods
Granulosa cells were collected from 45 PCOS patients under assisted reproductive technique (ART). Gene expression of Ahr downstream pathway was evaluated based on Reverse Transcription Q-PCR assay. Moreover the correlation was investigated between gene expression and hyperandrogenism, and oocyte developmental competency in PCOS.
Results
From the 45 PCOS patients, 26 (64.44%) had a high level of follicular fluid testosterone (FFT). Based on the FFT level, two groups of PCOS: HFT (high level of FFT) and non-HFT, were shown significant differences in oocyte and embryo quality, and fertilization and cleavage rates. Moreover, the mean relative expressions of Ahr and Arnt genes were significantly higher in HFT –PCOS group (p < 0.01 and p < 0.01) respectively. Also, the significant positive correlations were obtained for Ahr, Arnt, Cyp1A1, and Cyp1B1 with incidence of clinical hyperandrogenism and FFT level. Besides, our results showed that Ahr, Cyp1A1, and Cyp1B1 gene expression was correlated significantly with fertilization rate.
Conclusion
The present study suggested that hyperandrogenism could impair oocyte developmental competency via affecting Ahr signaling downstream pathway.
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Xu C, Cheng S, Chen K, Song Q, Liu C, Fan C, Zhang R, Zhu Q, Wu Z, Wang Y, Fan J, Zheng H, Lu L, Chen T, Zhao H, Jiao Y, Qu C. Sex Differences in Genomic Features of Hepatitis B-Associated Hepatocellular Carcinoma With Distinct Antitumor Immunity. Cell Mol Gastroenterol Hepatol 2022; 15:327-354. [PMID: 36272708 PMCID: PMC9772570 DOI: 10.1016/j.jcmgh.2022.10.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 10/13/2022] [Accepted: 10/13/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND & AIMS Aflatoxin exposure increases the risk for hepatocellular carcinoma (HCC) in hepatitis B virus (HBV)-infected individuals, particularly males. We investigated sex-based differences in the HCC genome and antitumor immunity. METHODS Whole-genome, whole-exome, and RNA sequencing were performed on 101 HCC patient samples (47 males, 54 females) that resulted from HBV infection and aflatoxin exposure from Qidong. Androgen on the expression of aflatoxin metabolism-related genes and nonhomologous DNA end joining (NHEJ) factors were examined in HBV-positive HCC cell lines, and further tested in tumor-bearing syngeneic mice. RESULTS Qidong HCC differed between males and females in genomic landscape and transcriptional dysfunction pathways. Compared with females, males expressed higher levels of aflatoxin metabolism-related genes, such as AHR and CYP1A1, and lower levels of NHEJ factors, such as XRCC4, LIG4, and MRE11, showed a signature of up-regulated type I interferon signaling/response and repressed antitumor immunity. Treatment with AFB1 in HBV-positive cells, the addition of 2 nmol/L testosterone to cultures significantly increased the expression of aflatoxin metabolism-related genes, but reduced NHEJ factors, resulting in more nuclear DNA leakage into cytosol to activate cGAS-STING. In syngeneic tumor-bearing mice that were administrated tamoxifen daily via oral gavage, favorable androgen signaling repressed NHEJ factor expression and activated cGAS-STING in tumors, increasing T-cell infiltration and improving anti-programmed cell death protein 1 treatment effect. CONCLUSIONS Androgen signaling in the context of genotoxic stress repressed DNA damage repair. The alteration caused more nuclear DNA leakage into cytosol to activate the cGAS-STING pathway, which increased T-cell infiltration into tumor mass and improved anti-programmed cell death protein 1 immunotherapy in HCCs.
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Affiliation(s)
- Chungui Xu
- State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Immunology Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Shaoyan Cheng
- State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Immunology Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Kun Chen
- State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Immunology Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Qianqian Song
- State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Chang Liu
- State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Immunology Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Chunsun Fan
- Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, Jiangsu Province, China
| | - Ruochan Zhang
- State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Immunology Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Qing Zhu
- State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Zhiyuan Wu
- State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Immunology Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yuting Wang
- State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Immunology Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Jian Fan
- Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, Jiangsu Province, China
| | - Hongwei Zheng
- Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, Jiangsu Province, China
| | - Lingling Lu
- Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, Jiangsu Province, China
| | - Taoyang Chen
- Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, Jiangsu Province, China
| | - Hong Zhao
- State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Department of Hepatobiliary Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
| | - Yuchen Jiao
- State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
| | - Chunfeng Qu
- State Key Lab of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Immunology Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
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Zhou Y, Zhu K, Wang Q, Chen M, He C, Yang C, Zuo Z. Aryl hydrocarbon receptor agonist diuron and its metabolites cause reproductive disorders in male marine medaka (Oryzias melastigma). CHEMOSPHERE 2022; 305:135388. [PMID: 35718029 DOI: 10.1016/j.chemosphere.2022.135388] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 06/05/2022] [Accepted: 06/14/2022] [Indexed: 06/15/2023]
Abstract
Diuron, a widely used phenylurea herbicide, has been frequently detected in marine organism and seawater all over the world. But the understanding of potential damage of diuron on reproduction in marine fish is currently not enough. Herein, marine medaka (Oryzias melastigma) were continuously exposed to 0, 5, 50, 500, and 5000 ng/L diuron from embryo (0 dpf) to adult (180 dpf) stage. The results suggested that diuron had an adverse influence on male reproduction for marine medaka, including decreased gonado somatic index, histological changes of testes, decreased mobility of sperm, and reduced fecundity through disrupting the balance of sex hormone and genes expression related to hypothalamus-pituitary-gonadal-liver (HPGL) axis. The reduced fecundity was reflected in abnormal sexual behaviors, further inhibited growth and development of F1 embryo and larvae. Moreover, the proportion of diuron metabolites (DCPMU and DCPU) was increased in fish, but the proportion of diuron was decreased with the increasing of exposure concentration. Diuron, DCPMU, and DCPU was identified as aryl hydrocarbon receptor agonist (AhR) agonist using in silico and in vivo models. DCPMU and DCPU induced the gene expression of AhR signaling and metabolizing enzymes (such as cyp1a1) in the livers. A great deal of major metabolites affected various organs related to HPGL axis of male marine medaka and led to serious reproductive disorders. Consequently, it reveals that long-term exposure to environmentally relevant concentrations of diuron and even AhR agonist pesticides pose a potential ecological risk for marine fish.
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Affiliation(s)
- Yixi Zhou
- State Key Laboratory of Cellular Stress Biology, United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Kongyang Zhu
- State Key Laboratory of Cellular Stress Biology, United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Qian Wang
- Key Laboratory of the Ministry of Education for Coastal and Wetland Ecosystems, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Meng Chen
- Key Laboratory of the Ministry of Education for Coastal and Wetland Ecosystems, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Chengyong He
- State Key Laboratory of Cellular Stress Biology, United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Chunyan Yang
- State Key Laboratory of Cellular Stress Biology, United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
| | - Zhenghong Zuo
- State Key Laboratory of Cellular Stress Biology, United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China; Key Laboratory of the Ministry of Education for Coastal and Wetland Ecosystems, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
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10
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Wang C, Zhang Y. Endoplasmic Reticulum Stress: A New Research Direction for Polycystic Ovary Syndrome? DNA Cell Biol 2022; 41:356-367. [PMID: 35353637 DOI: 10.1089/dna.2021.1050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is one of the most common gynecological endocrine disorders, with sporadic ovulation, excessive androgens, and polycystic ovarian changes as the main clinical manifestations. Due to the high heterogeneity of its clinical manifestations, the discussion on its pathogenesis has not been unified. Current research has found that genetic factors, hyperandrogenism, chronic inflammation and oxidative stress, insulin resistance, and obesity are strongly associated with PCOS. Recently, when studying the specific mechanisms of the abovementioned factors in PCOS, the biological response process of endoplasmic reticulum stress (ERS) has gradually come to researchers' attention, and several studies have confirmed the involvement of ERS in the pathogenesis of PCOS and the improvement of a series of pathological manifestations of PCOS after the application of ERS inhibitors, which may be a new entry point for the treatment of PCOS. In this article, we review the relationship between ERS and various pathogenic factors of PCOS.
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Affiliation(s)
- Chengzhe Wang
- Department of Gynecology of traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan City, China
| | - Yingjie Zhang
- Department of Gynecology of traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan City, China
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11
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Armouti M, Rodriguez-Esquivel M, Stocco C. Mechanism of negative modulation of FSH signaling by salt-inducible kinases in rat granulosa cells. Front Endocrinol (Lausanne) 2022; 13:1026358. [PMID: 36246922 PMCID: PMC9556844 DOI: 10.3389/fendo.2022.1026358] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 09/08/2022] [Indexed: 12/01/2022] Open
Abstract
The optimal development of preovulatory follicles needs follicle-stimulating hormone (FSH). Recent findings revealed that salt-inducible kinases (SIKs) inhibit FSH actions in humans and rodents. This report seeks to increase our understanding of the molecular mechanisms controlled by SIKs that participate in the inhibition of FSH actions in primary rat granulosa cells (GCs). The results showed that FSH causes a transient induction of Sik1 mRNA. In contrast, SIK inhibition had no effects on FSH receptor expression. Next, we determined whether SIK inhibition enhances the effect of several sequential direct activators of the FSH signaling pathway. The findings revealed that SIK inhibition stimulates the induction of steroidogenic genes by forskolin, cAMP, protein kinase A (PKA), and cAMP-response element-binding protein (CREB). Strikingly, FSH stimulation of CREB and AKT phosphorylation was not affected by SIK inhibition. Therefore, we analyzed the expression and activation of putative CREB cofactors and demonstrated that GCs express CREB-regulated transcriptional coactivators (CRTC2) and that FSH treatment and SIK inhibition increase the nuclear expression of this factor. We concluded that SIKs target the FSH pathway by affecting factors located between cAMP/PKA and CREB and propose that SIKs control the activity of CRTC2 in ovarian GCs. The findings demonstrate for the first time that SIKs blunt the response of GCs to FSH, cAMP, PKA, and CREB, providing further evidence for a crucial role for SIKs in regulating ovarian function and female fertility.
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12
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Kunitomi C, Harada M, Kusamoto A, Azhary JM, Nose E, Koike H, Xu Z, Urata Y, Takahashi N, Wada-Hiraike O, Hirota Y, Koga K, Fujii T, Osuga Y. Induction of aryl hydrocarbon receptor in granulosa cells by endoplasmic reticulum stress contributes to pathology of polycystic ovary syndrome. Mol Hum Reprod 2021; 27:gaab003. [PMID: 33493289 DOI: 10.1093/molehr/gaab003] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 01/04/2021] [Indexed: 12/12/2022] Open
Abstract
Recent studies have uncovered the critical role of aryl hydrocarbon receptor (AHR) in various diseases, including obesity and cancer progression, independent of its previously identified role as a receptor for endocrine-disrupting chemicals (EDCs). We previously showed that endoplasmic reticulum (ER) stress, a newly recognized local factor in the follicular microenvironment, is activated in granulosa cells from patients with polycystic ovary syndrome (PCOS) and a mouse model of the disease. By affecting diverse functions of granulosa cells, ER stress contributes to PCOS pathology. We hypothesized that expression of AHR and activation of its downstream signaling were upregulated by ER stress in granulosa cells, irrespective of the presence of EDCs, thereby promoting PCOS pathogenesis. In this study, we found that AHR, AHR nuclear translocator (ARNT), and AHR target gene cytochrome P450 1B1 (CYP1B1) were upregulated in the granulosa cells of PCOS patients and model mice. We examined CYP1B1 as a representative AHR target gene. AHR and ARNT were upregulated by ER stress in human granulosa-lutein cells (GLCs), resulting in an increase in the expression and activity of CYP1B1. Administration of the AHR antagonist CH223191 to PCOS mice restored estrous cycling and decreased the number of atretic antral follicles, concomitant with downregulation of AHR and CYP1B1 in granulosa cells. Taken together, our findings indicate that AHR activated by ER stress in the follicular microenvironment contributes to PCOS pathology, and that AHR represents a novel therapeutic target for PCOS.
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Affiliation(s)
- Chisato Kunitomi
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo, Tokyo 113-8655, Japan
| | - Miyuki Harada
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo, Tokyo 113-8655, Japan
| | - Akari Kusamoto
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo, Tokyo 113-8655, Japan
| | - Jerilee Mk Azhary
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo, Tokyo 113-8655, Japan
| | - Emi Nose
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo, Tokyo 113-8655, Japan
| | - Hiroshi Koike
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo, Tokyo 113-8655, Japan
| | - Zixin Xu
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo, Tokyo 113-8655, Japan
| | - Yoko Urata
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo, Tokyo 113-8655, Japan
| | - Nozomi Takahashi
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo, Tokyo 113-8655, Japan
| | - Osamu Wada-Hiraike
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo, Tokyo 113-8655, Japan
| | - Yasushi Hirota
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo, Tokyo 113-8655, Japan
| | - Kaori Koga
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo, Tokyo 113-8655, Japan
| | - Tomoyuki Fujii
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo, Tokyo 113-8655, Japan
| | - Yutaka Osuga
- Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Bunkyo, Tokyo 113-8655, Japan
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13
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Armouti M, Winston N, Hatano O, Hobeika E, Hirshfeld-Cytron J, Liebermann J, Takemori H, Stocco C. Salt-inducible Kinases Are Critical Determinants of Female Fertility. Endocrinology 2020; 161:5826400. [PMID: 32343771 PMCID: PMC7286620 DOI: 10.1210/endocr/bqaa069] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 04/21/2020] [Indexed: 12/28/2022]
Abstract
Follicle development is the most crucial step toward female fertility and is controlled mainly by follicle-stimulating hormone (FSH). In ovarian granulosa cells (GCs), FSH activates protein kinase A by increasing 3',5'-cyclic adenosine 5'-monophosphate (cAMP). Since cAMP signaling is impinged in part by salt-inducible kinases (SIKs), we examined the role of SIKs on the regulation of FSH actions. Here, we report that SIKs are essential for normal ovarian function and female fertility. All SIK isoforms are expressed in human and rodent GCs at different levels (SIK3>SIK2>SIK1). Pharmacological inhibition of SIK activity potentiated the stimulatory effect of FSH on markers of GC differentiation in mouse, rat, and human GCs and estradiol production in rat GCs. In humans, SIK inhibition strongly enhanced FSH actions in GCs of patients with normal or abnormal ovarian function. The knockdown of SIK2, but not SIK1 or SIK3, synergized with FSH on the induction of markers of GC differentiation. SIK inhibition boosted gonadotropin-induced GC differentiation in vivo, while the genomic knockout of SIK2 led to a significant increase in the number of ovulated oocytes. Conversely, SIK3 knockout females were infertile, FSH insensitive, and had abnormal folliculogenesis. These findings reveal novel roles for SIKs in the regulation of GC differentiation and female fertility, and contribute to our understanding of the mechanisms regulated by FSH. Furthermore, these data suggest that specific pharmacological modulation of SIK2 activity could be of benefit to treat ovulatory defects in humans and to increase the propagation of endangered species and farm mammals.
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Affiliation(s)
- Marah Armouti
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois
| | - Nicola Winston
- Department of Obstetrics and Gynecology, University of Illinois at Chicago College of Medicine. Chicago, Illinois
| | - Osamu Hatano
- Department of Basic Medicine, Nara Medical University, Nara, Japan
| | - Elie Hobeika
- Fertility Centers of Illinois, Chicago, Illinois
| | | | | | - Hiroshi Takemori
- Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu, Japan
| | - Carlos Stocco
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois
- Department of Obstetrics and Gynecology, University of Illinois at Chicago College of Medicine. Chicago, Illinois
- Correspondence: Carlos Stocco, Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612. E-mail:
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14
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Albumin is a secret factor involved in multidirectional interactions among the serotoninergic, immune and endocrine systems that supervises the mechanism of CYP1A and CYP3A regulation in the liver. Pharmacol Ther 2020; 215:107616. [PMID: 32590025 DOI: 10.1016/j.pharmthera.2020.107616] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 06/15/2020] [Indexed: 12/25/2022]
Abstract
This review focuses on albumin, which is involved in multidirectional interactions among the immune, endocrine and serotoninergic systems and supervises the regulation of cytochrome P450 (CYP) isoforms under conditions of both normal liver function and liver insufficiency. Special attention is paid to albumin, thyroid hormones, testosterone and tryptophan hydroxylase in these interactions as well as their potential roles in liver regeneration. The association of these factors with inflammation and the modification of the mechanism of hepatic drug-metabolizing CYP isoform regulation are also presented because changes in the expression of CYP isoforms in the liver may result in subsequent changes to a marker substance used for testing CYP activity, thus providing a simple way to control the liver regeneration process or the dangerous stimulation of hepatocarcinogenesis.
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15
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Puttabyatappa M, Matiller V, Stassi AF, Salvetti NR, Ortega HH, Padmanabhan V. Developmental Programming: Prenatal Testosterone Excess on Ovarian SF1/DAX1/FOXO3. Reprod Sci 2020; 27:342-354. [PMID: 32046386 DOI: 10.1007/s43032-019-00029-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 04/09/2019] [Indexed: 12/22/2022]
Abstract
Prenatal testosterone (T) excess, partly via androgenic programming, enhances follicular recruitment/persistence in sheep as in women with polycystic ovarian syndrome (PCOS). Decreased anti-Mullerian hormone (AMH) in early growing and increased AMH in antral follicles may underlie enhanced recruitment and persistence, respectively. Changes in AMH may be mediated by steroidogenic factor 1 (SF1), an enhancer of AMH, and dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1), that antagonizes SF1. Another mediator could be forkhead box 03 (FOXO3) which regulates follicular recruitment/atresia. To test if androgen-programmed changes in SF1, DAX1, and FOXO3 proteins contribute to follicular defects in prenatal T-treated sheep, ovaries from control, prenatal T-, and dihydrotestosterone (DHT)-treated (days 30-90 of gestation) animals at fetal day (FD) 90, FD140, and 1 and 2 years-of-age were studied. Prenatal T increased DAX1 in granulosa cells of primordial through large preantral and theca cells of large preantral follicles at FD140 and increased SF1 in the granulosa cells of preantral and antral and theca cells of large preantral follicle at 2 years-of-age. Prenatal T increased FOXO3 only in theca cells of preantral (FD140) and antral (2 years-of-age) follicles. Prenatal DHT increased DAX1 in granulosa cells from small preantral follicles at FD140 while increasing SF1 in granulosa cells from antral follicles at 1 year-of-age. These age-dependent changes in DAX1/SF1 partly via androgen-programming are consistent with changes in AMH and may contribute to the enhanced follicular recruitment/persistence, and multifollicular phenotype of prenatal T-treated females and may be of translational relevance to PCOS.
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Affiliation(s)
- Muraly Puttabyatappa
- Department of Pediatrics and the Reproductive Sciences Program, University of Michigan, Room 7510 MSRB I, 1150 Medical Center Drive, Ann Arbor, MI, 48109-5718, USA
| | - Valentina Matiller
- Instituto de Ciencias Veterinarias del Litoral (ICiVet-Litoral), Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Esperanza, Santa Fe, Argentina
| | - Antonela F Stassi
- Instituto de Ciencias Veterinarias del Litoral (ICiVet-Litoral), Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Esperanza, Santa Fe, Argentina
| | - Natalia R Salvetti
- Instituto de Ciencias Veterinarias del Litoral (ICiVet-Litoral), Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Esperanza, Santa Fe, Argentina
| | - Hugo H Ortega
- Instituto de Ciencias Veterinarias del Litoral (ICiVet-Litoral), Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Esperanza, Santa Fe, Argentina
| | - Vasantha Padmanabhan
- Department of Pediatrics and the Reproductive Sciences Program, University of Michigan, Room 7510 MSRB I, 1150 Medical Center Drive, Ann Arbor, MI, 48109-5718, USA.
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Villaseñor-Altamirano AB, Watson JD, Prokopec SD, Yao CQ, Boutros PC, Pohjanvirta R, Valdés-Flores J, Elizondo G. 2,3,7,8-Tetrachlorodibenzo-p-dioxin modifies alternative splicing in mouse liver. PLoS One 2019; 14:e0219747. [PMID: 31386671 PMCID: PMC6684058 DOI: 10.1371/journal.pone.0219747] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 07/02/2019] [Indexed: 12/22/2022] Open
Abstract
Alternative splicing is a co-transcriptional mechanism that generates protein diversity by including or excluding exons in different combinations, thereby expanding the diversity of protein isoforms of a single gene. Abnormalities in this process can result in deleterious effects to human health, and several xenobiotics are known to interfere with splicing regulation through multiple mechanisms. These changes could lead to human diseases such as cancer, neurological disorders, autoimmune diseases, and developmental disorders. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant generated as a byproduct of various industrial activities. Exposure to this dioxin has been linked to a wide range of pathologies through the alteration of multiple cellular processes. However, the effects of TCDD exposure on alternative splicing have not yet been studied. Here, we investigated whether a single po. dose of 5 μg/kg or 500 μg/kg TCDD influence hepatic alternative splicing in adult male C57BL/6Kou mouse. We identified several genes whose alternative splicing of precursor messenger RNAs was modified following TCDD exposure. In particular, we demonstrated that alternative splicing of Cyp1a1, Ahrr, and Actn1 was significantly altered after TCDD treatment. These findings show that the exposure to TCDD has an impact on alternative-splicing, and suggest a new avenue for understanding TCDD-mediated toxicity and pathogenesis.
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Affiliation(s)
- Ana B. Villaseñor-Altamirano
- Cell Biology Department, Center for Research and Advanced Studies of the National Polytechnic Institute, CINVESTAN-IPN, Mexico City, Mexico
- International Laboratory for Human Genome Research, National Autonomous University of Mexico, Queretaro, Mexico
| | | | | | - Cindy Q. Yao
- Ontario Institute for Cancer Research, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Paul C. Boutros
- Ontario Institute for Cancer Research, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, California, United States of America
| | - Raimo Pohjanvirta
- Laboratory of Toxicology, National Institute for Health and Welfare, Kuopio, Finland
- Department of Food Hygiene and Environmental Health, University of Helsinki, Helsinki, Finland
| | - Jesús Valdés-Flores
- Biochemistry Department, Center for Research and Advanced Studies of the National Polytechnic Institute, CINVESTAV-IPN, Mexico City, Mexico
| | - Guillermo Elizondo
- Cell Biology Department, Center for Research and Advanced Studies of the National Polytechnic Institute, CINVESTAN-IPN, Mexico City, Mexico
- * E-mail:
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17
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Jackson EN, Thatcher SE, Larian N, English V, Soman S, Morris AJ, Weng J, Stromberg A, Swanson HI, Pearson K, Cassis LA. Effects of Aryl Hydrocarbon Receptor Deficiency on PCB-77-Induced Impairment of Glucose Homeostasis during Weight Loss in Male and Female Obese Mice. ENVIRONMENTAL HEALTH PERSPECTIVES 2019; 127:77004. [PMID: 31306034 PMCID: PMC6794491 DOI: 10.1289/ehp4133] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 05/26/2019] [Accepted: 06/14/2019] [Indexed: 05/29/2023]
Abstract
BACKGROUND Lipophilic polychlorinated biphenyls (PCBs) accumulate with obesity, but during weight loss, liberated PCBs act as ligands of the aryl hydrocarbon receptor (AhR) to negatively influence health. Previous studies demonstrated that PCB-77 administration to obese male mice impaired glucose tolerance during weight loss. Recent studies indicate higher toxic equivalencies of dioxin-like PCBs in exposed females than males. OBJECTIVES We compared effects of PCB-77 on weight gain or loss and glucose homeostasis in male vs. female mice. We defined effects of AhR deficiency during weight gain or loss in male and female mice exposed to PCB-77. METHODS Study design was vehicle (VEH) or PCB-77 administration while fed a high-fat (HF) diet for 12 wk, followed by weight loss for 4 wk. The following groups were examined: male and female C57BL/6 mice administered VEH or PCB-77, female [Formula: see text] and [Formula: see text] mice administered VEH or PCB-77, and male [Formula: see text] and [Formula: see text] mice administered PCB-77. Glucose tolerance was quantified during weight gain (week 11) and loss (week 15); liver and adipose AhR and IRS2 (insulin receptor substrate 2) mRNA abundance, and PCB-77 concentrations were quantified at week 16. RESULTS PCB-77 attenuated development of obesity in females but not males. During weight loss, PCB-77 impaired glucose tolerance of males. AhR-deficient females (VEH) were resistant to diet-induced obesity. Compared with VEH-treated mice, HF-fed [Formula: see text] females treated with PCB-77 has less weight gain, and [Formula: see text] females had greater weight gain. During weight loss, [Formula: see text] females but not [Formula: see text] males treated with PCB-77 exhibited impaired glucose tolerance. In [Formula: see text] females administered PCB-77, IRS2 mRNA abundance was lower in adipose tissue compared with VEH-treated mice. CONCLUSION Male and female mice responded differently to PCB-77 and AhR deficiency in body weight (BW) regulation and glucose homeostasis. AhR deficiency reversed PCB-77-induced glucose impairment of obese males losing weight but augmented glucose intolerance of females. These results demonstrate sex differences in PCB-77-induced regulation of glucose homeostasis of mice. https://doi.org/10.1289/EHP4133.
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Affiliation(s)
- Erin N. Jackson
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA
| | - Sean E. Thatcher
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA
| | - Nika Larian
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA
| | - Victoria English
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA
| | - Sony Soman
- Department of Internal Medicine, University of Kentucky, Lexington, Kentucky, USA
| | - Andrew J. Morris
- Department of Internal Medicine, University of Kentucky, Lexington, Kentucky, USA
| | - Jiaying Weng
- Department of Statistics, University of Kentucky, Lexington, Kentucky, USA
| | - Arnold Stromberg
- Department of Statistics, University of Kentucky, Lexington, Kentucky, USA
| | - Hollie I. Swanson
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA
| | - Kevin Pearson
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA
| | - Lisa A. Cassis
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA
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18
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Zajda K, Rak A, Ptak A, Gregoraszczuk EL. Compounds of PAH mixtures dependent interaction between multiple signaling pathways in granulosa tumour cells. Toxicol Lett 2019; 310:14-22. [PMID: 30980910 DOI: 10.1016/j.toxlet.2019.04.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 03/22/2019] [Accepted: 04/08/2019] [Indexed: 01/02/2023]
Abstract
Mechanism of PAH mixtures, using granulosa tumour cells, was investigated. Cells were exposed to a mixture of all 16 priority PAHs (M1) or a mixture of five PAHs not classified as human carcinogens (M2). The effect of siAHR, siAHRR and siNFKB2 on the expression of CYP1A1, CYP1B1, GSTM1, ERα, AR and cell proliferation was described. M1 decreased AhR and CYP1A1, while increased AhRR and ARNT expression. M2 also decreased AhR and CYP1A1 but had no effect on AhRR expression. siAHRR reversed the inhibitory effect of M1 on AhR and CYP1A1,while inhibitory effect of M2 was still observed. siNFKB2 reversed inhibitory effect of both mixtures on AhR and CYP1A1 expression and stimulatory effect of M1 on AhRR expression. siAHR reversed stimulatory effect of both mixtures on ERα expression. Stimulatory effect of M1 on cell proliferation was not observed in siAHR, was still observed in siESR1 cells. M2 had no effect on cell proliferation, however stimulatory effect was appeared in siAHR and siESR1cells. In conclusion: M1 by activation of AhRR and NFkB p52, but M2 only by activation of NFκB attenuated AhR signalling and ligand-induced CYP1A1 expression. Interaction between AhR and ER following M1 and M2 exposure is primarily initiated through AhR.
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Affiliation(s)
- K Zajda
- Department of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Kraków, Poland
| | - A Rak
- Department of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Kraków, Poland
| | - A Ptak
- Department of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Kraków, Poland
| | - E L Gregoraszczuk
- Department of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Kraków, Poland.
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Chung WM, Ho YP, Chang WC, Dai YC, Chen L, Hung YC, Ma WL. Increase Paclitaxel Sensitivity to Better Suppress Serous Epithelial Ovarian Cancer via Ablating Androgen Receptor/Aryl Hydrocarbon Receptor-ABCG2 Axis. Cancers (Basel) 2019; 11:cancers11040463. [PMID: 30986993 PMCID: PMC6521308 DOI: 10.3390/cancers11040463] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 03/11/2019] [Accepted: 03/27/2019] [Indexed: 12/15/2022] Open
Abstract
Background: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies and presents chemoresistance after chemotherapy treatment. Androgen receptor (AR) has been known to participate in proliferation. Yet the mechanisms of the resistance of this drug and its linkage to the AR remains unclear. Methods: To elucidate AR-related paclitaxel sensitivity, co-IP, luciferase reporter assay and ChIP assay were performed to identify that AR direct-regulated ABCG2 expression under paclitaxel treatment. IHC staining by AR antibody presented higher AR expression in serous-type patients than other types. AR degradation enhancer (ASC-J9) was used to examine paclitaxel-associated and paclitaxel-resistant cytotoxicity in vitro and in vivo. Results: We found AR/aryl hydrocarbon receptor (AhR)-mediates ABCG2 expression and leads to a change in paclitaxel cytotoxicity/sensitivity in EOC serous subtype cell lines. Molecular mechanism study showed that paclitaxel activated AR transactivity and bound to alternative ARE in the ABCG2 proximal promoter region. To identify AR as a potential therapeutic target, the ASC-J9 was used to re-sensitize paclitaxel-resistant EOC tumors upon paclitaxel treatment in vitro and in vivo. Conclusion: The results demonstrated that activation of AR transactivity beyond the androgen-associated biological effect. This novel AR mechanism explains that degradation of AR is the most effective therapeutic strategy for treating AR-positive EOC serous subtype.
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Affiliation(s)
- Wei-Min Chung
- Graduate Institution of Clinical Medical Science, and Graduate Institute of BioMedical Sciences, School of Medicine, China Medical University, Taichung 40403, Taiwan.
- Sex Hormone Research Center, Department of Obstetrics and Gynecology, and Reproductive Medicine Center, China Medical University Hospital, Taichung 40403, Taiwan.
| | - Yen-Ping Ho
- Sex Hormone Research Center, Department of Obstetrics and Gynecology, and Reproductive Medicine Center, China Medical University Hospital, Taichung 40403, Taiwan.
| | - Wei-Chun Chang
- Graduate Institution of Clinical Medical Science, and Graduate Institute of BioMedical Sciences, School of Medicine, China Medical University, Taichung 40403, Taiwan.
- Sex Hormone Research Center, Department of Obstetrics and Gynecology, and Reproductive Medicine Center, China Medical University Hospital, Taichung 40403, Taiwan.
| | - Yuan-Chang Dai
- Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi City 60002, Taiwan.
| | - Lumin Chen
- Sex Hormone Research Center, Department of Obstetrics and Gynecology, and Reproductive Medicine Center, China Medical University Hospital, Taichung 40403, Taiwan.
- Department of OBs & GYN, BenQ Medical Center, Suzhou 215004, Jiangsu Province, China.
| | - Yao-Ching Hung
- Graduate Institution of Clinical Medical Science, and Graduate Institute of BioMedical Sciences, School of Medicine, China Medical University, Taichung 40403, Taiwan.
- Sex Hormone Research Center, Department of Obstetrics and Gynecology, and Reproductive Medicine Center, China Medical University Hospital, Taichung 40403, Taiwan.
| | - Wen-Lung Ma
- Graduate Institution of Clinical Medical Science, and Graduate Institute of BioMedical Sciences, School of Medicine, China Medical University, Taichung 40403, Taiwan.
- Sex Hormone Research Center, Department of Obstetrics and Gynecology, and Reproductive Medicine Center, China Medical University Hospital, Taichung 40403, Taiwan.
- Department of Nursing, Asia University, Taichung 41354, Taiwan.
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20
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Xiao L, Wang Y, Xu K, Hu H, Xu Z, Wu D, Wang Z, You W, Ng CF, Yu S, Chan FL. Nuclear Receptor LRH-1 Functions to Promote Castration-Resistant Growth of Prostate Cancer via Its Promotion of Intratumoral Androgen Biosynthesis. Cancer Res 2018; 78:2205-2218. [PMID: 29438990 DOI: 10.1158/0008-5472.can-17-2341] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 12/27/2017] [Accepted: 02/05/2018] [Indexed: 11/16/2022]
Abstract
Targeting of steroidogenic enzymes (e.g., abiraterone acetate targeting CYP17A1) has been developed as a novel therapeutic strategy against metastatic castration-resistant prostate cancer (CRPC). However, resistance to steroidal inhibitors inevitably develops in patients, the mechanisms of which remain largely unknown. Liver receptor homolog-1 (LRH-1, NR5A2) is a nuclear receptor, originally characterized as an important regulator of some liver-specific metabolic genes. Here, we report that LRH-1, which exhibited an increased expression pattern in high-grade prostate cancer and CRPC xenograft models, functions to promote de novo androgen biosynthesis via its direct transactivation of several key steroidogenic enzyme genes, elevating intratumoral androgen levels and reactivating AR signaling in CRPC xenografts as well as abiraterone-treated CRPC tumors. Pharmacologic inhibition of LRH-1 activity attenuated LRH-1-mediated androgen deprivation and anti-androgen resistance of prostate cancer cells. Our findings not only demonstrate the significant role of LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management.Significance: These findings not only demonstrate the significant role of the nuclear receptor LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management. Cancer Res; 78(9); 2205-18. ©2018 AACR.
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Affiliation(s)
- Lijia Xiao
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China.,Department of Clinical Laboratory Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Yuliang Wang
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Kexin Xu
- Department of Urology, Peking University People's Hospital, Beijing, China
| | - Hao Hu
- Department of Urology, Peking University People's Hospital, Beijing, China
| | - Zhenyu Xu
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Dinglan Wu
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Zhu Wang
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Wenxing You
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Chi-Fai Ng
- Department of Surgery, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
| | - Shan Yu
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China.
| | - Franky Leung Chan
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China.
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21
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Abstract
The aryl hydrocarbon receptor (AhR) is now recognized as an important physiological regulator in the immune and reproductive systems, and in the development of the liver and vascular system. AhR regulates cell cycle, cell proliferation, and differentiation through interacting with other signaling pathways, like estrogen receptor α (ERα), androgen receptor (AR), and Notch signaling. In the present study, we investigated Notch and estrogen signaling in AhR-/- mice. We found low fertility with degenerative changes in the testes, germ cell apoptosis, and a reduced number of early spermatids. There was no change in aromatase, AR, ERα, or ERβ expression in the testis and no detectable change in serum estrogen levels. However, expression of Notch receptors (Notch1 and Notch3) and their target Hairy and Enhancer of Split homolog 1 (HES1) was reduced. In addition, the testosterone level was slightly reduced in the serum. In the mammary fat pad, AhR appeared to regulate estrogen signaling because, in AhR-/- males, there was significant growth of the mammary ducts with high expression of ERα in the ductal epithelium. The enhanced mammary ductal growth appears to be related to overexpression of ERα accompanied by a high proliferation index, whereas the reduced fertility appears to be related defects in Notch signaling that leads to reduced expression of HES1 and, consequently, early maturation of spermatocytes and a depletion of primary spermatids. Previous reports have indicated that AhR pathway is associated with infertility in men. Our results provide a mechanistic explanation for this defect.
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Activational action of testosterone on androgen receptors protects males preventing temporomandibular joint pain. Pharmacol Biochem Behav 2016; 152:30-35. [PMID: 27461546 DOI: 10.1016/j.pbb.2016.07.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 06/30/2016] [Accepted: 07/22/2016] [Indexed: 01/31/2023]
Abstract
BACKGROUND Testosterone protects male rats from Temporomandibular Joint (TMJ) pain. This study investigated whether this protective effect is mediated by an organizational action of testosterone during nervous system development, by central estrogen and androgen receptors and by the 5α-reduced metabolite of testosterone, dihydrotestosterone. METHODS A pharmacological approach was used to assess the ability of the androgen receptor antagonist flutamide, the estrogen receptor antagonist ICI 182 780 and the 5-α reductase inhibitor dutasteride to block the protective effect of testosterone, evaluated through the behavioral response induced by a TMJ injection of 0.5% formalin. Flutamide and ICI 182 780 were injected into the medullary subarachnoid space, and dutasteride and testosterone were systemically administered. RESULTS The TMJ injection of 0.5% formalin induced a significant nociceptive behavioral response in gonadectomized male and naïve female, but not in sham gonadectomized male rats, confirming that endogenous testosterone prevents TMJ nociception in males. Testosterone administration prevented formalin-induced TMJ nociception in males gonadectomized either in the neonatal (at the day of birth) or adult period and in naïve female rats, suggesting that the protective effect of testosterone on TMJ nociception does not depend on its organizational actions during critical periods of development. The administration of flutamide and dutasteride but not of ICI 182 780 blocked the protective effect of testosterone. CONCLUSIONS We conclude that the protective effect of testosterone on TMJ nociception depends on activational actions of dihydrotestosterone on androgen receptors rather than on organizational androgenic actions during central nervous system development or estrogenic actions.
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Barć J, Gregoraszczuk EL. Halowax 1051 affects steroidogenesis by down-regulation of aryl hydrocarbon and estrogen receptors and up-regulation of androgen receptor in porcine ovarian follicles. CHEMOSPHERE 2016; 144:467-474. [PMID: 26386772 DOI: 10.1016/j.chemosphere.2015.09.026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 09/01/2015] [Accepted: 09/06/2015] [Indexed: 06/05/2023]
Abstract
Polychlorinated naphthalenes (PCNs) are thought to interact with the aryl hydrocarbon receptor (AHR) and to have enzyme-inducing properties comparable to polychlorinated dibenzo-p-dioxins, therefore activation of steroid hormone receptors in endocrine tissues is also possible. The aim of the present study was to examine the effects of PCNs mixture, Halowax 1051 on gene and protein expression of receptors: estradiol (ERα/β), androgen (AR) and AHRGene expression was evaluated by real-time PCR after 6 h of exposition and protein expression by Western blot after 24 h. Levels of sex steroids: androstenedione (A4), estradiol (E2) and testosterone (T) were measured by enzyme immunoassays. Results of the data show down-regulation of AHR gene expression after 6 h in parallel with an inhibition in AHR protein expression at doses 10 pg-10 ng/mL, down-regulation of ER at all doses used, and up-regulation of AR gene expression at doses 1 and 10 ng/mL without affecting their protein expression. To indicate the involvement of AHR, ERs and AR in the impact of PCNs on steroidogenesis, we used their specific blockers. Blocker of AHR reversed the inhibitory effect of Halowax 1051 on A4 secretion, and strengthened its effect on T secretion. Blockers of both ER and AR had no effect on Halowax 1051 action on steroids secretion. The results of this study suggest that AHR is involved in the effect of PCNs on steroidogenesis in the ovary. Additionally, we propose that cross-talk between AHR-ER and AHR-AR receptors mediates the effects of Halowax 1051 on ovarian follicles.
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Affiliation(s)
- Justyna Barć
- Department of Physiology and Toxicology of Reproduction, Institute of Zoology, Jagiellonian University in Kraków, Kraków, Poland.
| | - Ewa Lucja Gregoraszczuk
- Department of Physiology and Toxicology of Reproduction, Institute of Zoology, Jagiellonian University in Kraków, Kraków, Poland
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24
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Kanda T, Yokosuka O. The androgen receptor as an emerging target in hepatocellular carcinoma. J Hepatocell Carcinoma 2015; 2:91-9. [PMID: 27508198 PMCID: PMC4918288 DOI: 10.2147/jhc.s48956] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the male-dominant liver diseases with poor prognosis, although treatments for HCC have been progressing in the past decades. Androgen receptor (AR) is a member of the nuclear receptor superfamily. Previous studies reported that AR was expressed in human HCC and non-HCC tissues. AR is activated both ligand-dependently and ligand-independently. The latter is associated with a mitogen-activated protein kinase–, v-akt murine thymoma viral oncogene homolog 1–, or signal-transducer and activator of transcription–signaling pathway, which has been implicated in the development of HCC. It has been reported that more than 200 RNA expression levels are altered by androgen treatment. In the liver, androgen-responsive genes are cytochrome P450s, transforming growth factor β, vascular endothelial growth factor, and glucose-regulated protein 78 kDa, which are also associated with human hepatocarcinogenesis. Recent studies also revealed that AR plays a role in cell migration and metastasis. It is possible that cross-talk among AR-signaling, endoplasmic reticulum stress, and innate immune response is important for human hepatocarcinogenesis and HCC development. This review shows that AR could play a potential role in human HCC and represent one of the important target molecules for the treatment of HCC.
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Affiliation(s)
- Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
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25
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Choi J, Psarommatis B, Gao YR, Zheng Y, Handelsman DJ, Simanainen U. The role of androgens in experimental rodent mammary carcinogenesis. Breast Cancer Res 2014; 16:483. [PMID: 25928046 PMCID: PMC4429669 DOI: 10.1186/s13058-014-0483-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Breast cancer is currently the most frequent, fatal cancer of women in western countries. While estrogens have a widely understood involvement in breast cancer, a significant but not yet fully understood role for androgens has also been suggested. The principal androgen, testosterone, is the obligate steroidal precursor of estradiol, but can equally be metabolized into dihydrotestosterone, a more potent, pure androgen. Both androgens exert their distinctive biological effects via the androgen receptor, which is coexpressed with estrogen receptor alpha in 80 to 90% of breast cancers. The hormonal control of breast development and pathology has been examined experimentally through the use of animal models, notably mice and rats. This review summarizes the data from experimental rodent models on the effects of androgens in experimental breast cancer, aiming to address the importance of androgens and the androgen receptor in the origins and pathogenesis of breast cancers, as well as to discuss potential biomarker and therapeutic opportunities arising from novel insights based on the experimental research.
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Affiliation(s)
- Jaesung Choi
- ANZAC Research Institute, University of Sydney, Sydney, NSW, 2139, Australia.
| | - Basil Psarommatis
- ANZAC Research Institute, University of Sydney, Sydney, NSW, 2139, Australia.
| | - Yan Ru Gao
- ANZAC Research Institute, University of Sydney, Sydney, NSW, 2139, Australia.
| | - Yu Zheng
- ANZAC Research Institute, University of Sydney, Sydney, NSW, 2139, Australia.
| | - David J Handelsman
- ANZAC Research Institute, University of Sydney, Sydney, NSW, 2139, Australia.
| | - Ulla Simanainen
- ANZAC Research Institute, University of Sydney, Sydney, NSW, 2139, Australia.
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26
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Abstract
For many decades, elevated androgens in women have been associated with poor reproductive health. However, recent studies have shown that androgens play a crucial role in women's fertility. The following review provides an overall perspective about how androgens and androgen receptor-mediated actions regulate normal follicular development, as well as discuss emerging concepts, latest perceptions, and controversies regarding androgen actions and signaling in the ovary.
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Affiliation(s)
- Hen Prizant
- Division of Endocrinology and MetabolismDepartment of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, PO Box 693, Rochester, New York 14642, USACenter for Human ReproductionNew York, New York 10021, USA
| | - Norbert Gleicher
- Division of Endocrinology and MetabolismDepartment of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, PO Box 693, Rochester, New York 14642, USACenter for Human ReproductionNew York, New York 10021, USA
| | - Aritro Sen
- Division of Endocrinology and MetabolismDepartment of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, PO Box 693, Rochester, New York 14642, USACenter for Human ReproductionNew York, New York 10021, USADivision of Endocrinology and MetabolismDepartment of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, PO Box 693, Rochester, New York 14642, USACenter for Human ReproductionNew York, New York 10021, USA
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27
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Gibson DA, Simitsidellis I, Collins F, Saunders PTK. Evidence of androgen action in endometrial and ovarian cancers. Endocr Relat Cancer 2014; 21:T203-18. [PMID: 24623742 DOI: 10.1530/erc-13-0551] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Endometrial cancer (EC) and ovarian cancer are common gynaecological malignancies. The impact of androgen action in these cancers is poorly understood; however, there is emerging evidence to suggest that targeting androgen signalling may be of therapeutic benefit. Epidemiological evidence suggests that there is an increased risk of EC associated with exposure to elevated levels of androgens, and genetic variants in genes related to both androgen biosynthesis and action are associated with an increased risk of both EC and ovarian cancer. Androgen receptors (ARs) may be a potential therapeutic target in EC due to reported anti-proliferative activities of androgens. By contrast, androgens may promote growth of some ovarian cancers and anti-androgen therapy has been proposed. Introduction of new therapies targeting ARs expressed in EC or ovarian cancer will require a much greater understanding of the impacts of cell context-specific AR-dependent signalling and how ARs can crosstalk with other steroid receptors during progression of disease. This review considers the evidence that androgens may be important in the aetiology of EC and ovarian cancer with discussion of evidence for androgen action in normal and malignant endometrial and ovarian tissue.
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Affiliation(s)
- Douglas A Gibson
- MRC Centre for Reproductive HealthThe University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Ioannis Simitsidellis
- MRC Centre for Reproductive HealthThe University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Frances Collins
- MRC Centre for Reproductive HealthThe University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Philippa T K Saunders
- MRC Centre for Reproductive HealthThe University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
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28
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Kanda T, Jiang X, Yokosuka O. Androgen receptor signaling in hepatocellular carcinoma and pancreatic cancers. World J Gastroenterol 2014; 20:9229-9236. [PMID: 25071315 PMCID: PMC4110552 DOI: 10.3748/wjg.v20.i28.9229] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 03/07/2014] [Accepted: 04/30/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) and pancreatic cancer remain difficult to treat, and despite the ongoing development of new treatments, the overall survival rate has only modestly improved over the past decade. Liver and pancreatic progenitors commonly develop from endoderm cells in the embryonic foregut. A previous study showed that HCC and pancreatic cancer cell lines variably express androgen receptor (AR), and these cancers and the surrounding tissues also express AR. AR is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily. Androgen response element is present in regulatory elements on the AR-responsive target genes, such as transforming growth factor beta-1 (TGF beta-1) and vascular endothelial growth factor (VEGF). It is well known that the activation of AR is associated with human carcinogenesis in prostate cancer as well as HCC and pancreatic cancer and that GRP78, TGF beta, and VEGF all play important roles in carcinogenesis and cancer development in these cancers. HCC is a male-dominant cancer irrespective of its etiology. Previous work has reported that vertebrae forkhead box A 1/2 are involved in estrogen receptors and/or AR signaling pathways, which may contribute to the gender differences observed with HCC. Our recent work also showed that AR has a critical role in pancreatic cancer development, despite pancreatic cancer not being a male dominant cancer. Aryl hydrocarbon (or dioxin) receptor is also involved in both HCC and pancreatic cancer through the formation of complex with AR. It is possible that AR might be involved in their carcinogenesis through major histocompatibility complex class I chain-related gene A/B. This review article describes AR and its role in HCC and pancreatic cancer and suggests that more specific AR signaling-inhibitors may be useful in the treatment of these "difficult to treat" cancers.
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