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Chaudhry KA, Bianchi-Smiraglia A. The aryl hydrocarbon receptor as a tumor modulator: mechanisms to therapy. Front Oncol 2024; 14:1375905. [PMID: 38807762 PMCID: PMC11130384 DOI: 10.3389/fonc.2024.1375905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 05/03/2024] [Indexed: 05/30/2024] Open
Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is widely recognized to play important, but complex, modulatory roles in a variety of tumor types. In this review, we comprehensively summarize the increasingly controversial role of AhR as a tumor regulator and the mechanisms by which it alters tumor progression based on the cancer cell type. Finally, we discuss new and emerging strategies to therapeutically modulate AhR, focusing on novel agents that hold promise in current human clinical trials as well as existing FDA-approved drugs that could potentially be repurposed for cancer therapy.
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Affiliation(s)
| | - Anna Bianchi-Smiraglia
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, NY, United States
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2
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Inyang I, White HE, Timme K, Keating AF. Biological sex differences in hepatic response to in utero dimethylbenz(a)anthracene exposure. Reprod Toxicol 2024; 124:108553. [PMID: 38307155 DOI: 10.1016/j.reprotox.2024.108553] [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: 09/19/2023] [Revised: 01/24/2024] [Accepted: 01/26/2024] [Indexed: 02/04/2024]
Abstract
Fetal hepatic dimethylbenz(a)anthracene (DMBA) biotransformation is not defined, thus, this study investigated whether the fetal liver metabolizes DMBA and differs with biological sex. KK.Cg-a/a (lean; n = 20) or KK.Cg-Ay/J (obese; n = 20) pregnant mice were exposed to corn oil (CT) or DMBA (1 mg/kg bw/day) by intraperitoneal injection (n = 10/treatment) from gestation day 7-14. Postnatal day 2 male or female offspring livers were collected. Total RNA (n = 6) and protein (n = 6) were analyzed via a PCR-based array or LC-MS/MS, respectively. The level of Mgst3 was lower (P < 0.05) in livers of female compared to male offspring. Furthermore, in utero DMBA exposure increased (P < 0.1) Cyp2c29 and Gpx3 levels (P < 0.05) in female offspring. In male offspring, the abundance of Ahr, Comt (P < 0.1), Alox5, and Asna1 (P < 0.05) decreased due to DMBA exposure. Female and male offspring had 34 and 21 hepatic proteins altered (P < 0.05) by in utero DMBA exposure, respectively. Opposing patterns for hepatic CD81 and KRT78 occurred, being decreased in females but increased in males, while YWHAG was decreased by DMBA exposure in both. Functional KEGG pathway analysis identified enrichment of 26 and 13 hepatic metabolic proteins in male and female offspring, respectively, due to in utero DMBA exposure. In silico transcription factor analysis of differentially expressed proteins predicted involvement of female NRF1 but male AHR. Thus, hepatic biological sex differences and capacity to respond to toxicants in utero are supported.
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Affiliation(s)
| | - Hunter E White
- Department of Animal Science, Iowa State University, USA
| | - Kelsey Timme
- Department of Animal Science, Iowa State University, USA
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3
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Hou Y, Li J, Ying S. Tryptophan Metabolism and Gut Microbiota: A Novel Regulatory Axis Integrating the Microbiome, Immunity, and Cancer. Metabolites 2023; 13:1166. [PMID: 37999261 PMCID: PMC10673612 DOI: 10.3390/metabo13111166] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 11/16/2023] [Accepted: 11/18/2023] [Indexed: 11/25/2023] Open
Abstract
Tryptophan metabolism and gut microbiota form an integrated regulatory axis that impacts immunity, metabolism, and cancer. This review consolidated current knowledge on the bidirectional interactions between microbial tryptophan processing and the host. We focused on how the gut microbiome controls tryptophan breakdown via the indole, kynurenine, and serotonin pathways. Dysbiosis of the gut microbiota induces disruptions in tryptophan catabolism which contribute to disorders like inflammatory conditions, neuropsychiatric diseases, metabolic syndromes, and cancer. These disruptions affect immune homeostasis, neurotransmission, and gut-brain communication. Elucidating the mechanisms of microbial tryptophan modulation could enable novel therapeutic approaches like psychobiotics and microbiome-targeted dietary interventions. Overall, further research on the microbiota-tryptophan axis has the potential to revolutionize personalized diagnostics and treatments for improving human health.
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Affiliation(s)
- Yingjian Hou
- Target Discovery Center, China Pharmaceutical University, Nanjing 211198, China;
| | - Jing Li
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha 410000, China
| | - Shuhuan Ying
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
- Shanghai Bocimed Pharmaceutical Research Co., Ltd., Shanghai 201203, China
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4
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Baez-Gonzalez AS, Carrazco-Carrillo JA, Figueroa-Gonzalez G, Quintas-Granados LI, Padilla-Benavides T, Reyes-Hernandez OD. Functional effect of indole-3 carbinol in the viability and invasive properties of cultured cancer cells. Biochem Biophys Rep 2023; 35:101492. [PMID: 37304131 PMCID: PMC10250583 DOI: 10.1016/j.bbrep.2023.101492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/16/2023] [Accepted: 05/18/2023] [Indexed: 06/13/2023] Open
Abstract
Cancer treatment typically involves multiple strategies, such as surgery, radiotherapy, and chemotherapy, to remove tumors. However, chemotherapy often causes side effects, and there is a constant search for new drugs to alleviate them. Natural compounds are a promising alternative to this problem. Indole-3-carbinol (I3C) is a natural antioxidant agent that has been studied as a potential cancer treatment. I3C is an agonist of the aryl hydrocarbon receptor (AhR), a transcription factor that plays a role in the expression of genes related to development, immunity, circadian rhythm, and cancer. In this study, we investigated the effect of I3C on cell viability, migration, invasion properties, as well as mitochondrial integrity in hepatoma, breast, and cervical cancer cell lines. We found that all tested cell lines showed impaired carcinogenic properties and alterations in mitochondrial membrane potential after treatment with I3C. These results support the potential use of I3C as a supplementary treatment for various types of cancer.
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Affiliation(s)
- Andrea S. Baez-Gonzalez
- Wesleyan University, 52 Lawn Ave, Middletown, CT, 06459, USA
- Universidad Nacional Autónoma de Mexico, Facultad de Estudios Superiores Zaragoza, Mexico City, Mexico
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5
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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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6
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Nguyen BD, Stevens BL, Elson DJ, Finlay D, Gamble J, Kopparapu P, Tanguay RL, Buermeyer AB, Kerkvliet NI, Kolluri SK. 11-Cl-BBQ, a select modulator of AhR-regulated transcription, suppresses lung cancer cell growth via activation of p53 and p27 Kip1. FEBS J 2023; 290:2064-2084. [PMID: 36401795 PMCID: PMC10807707 DOI: 10.1111/febs.16683] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 09/01/2022] [Accepted: 11/17/2022] [Indexed: 11/21/2022]
Abstract
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and functions as a tumour suppressor in different cancer models. In the present study, we report detailed characterization of 11-chloro-7H-benzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (11-Cl-BBQ) as a select modulator of AhR-regulated transcription (SMAhRT) with anti-cancer actions. Treatment of lung cancer cells with 11-Cl-BBQ induced potent and sustained AhR-dependent anti-proliferative effects by promoting G1 phase cell cycle arrest. Investigation of 11-Cl-BBQ-induced transcription in H460 cells with or without the AhR expression by RNA-sequencing revealed activation of p53 signalling. In addition, 11-Cl-BBQ suppressed multiple pathways involved in DNA replication and increased expression of cyclin-dependent kinase inhibitors, including p27Kip1 , in an AhR-dependent manner. CRISPR/Cas9 knockout of individual genes revealed the requirement for both p53 and p27Kip1 for the AhR-mediated anti-proliferative effects. Our results identify 11-Cl-BBQ as a potential lung cancer therapeutic, highlight the feasibility of targeting AhR and provide important mechanistic insights into AhR-mediated-anticancer actions.
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Affiliation(s)
- Bach D. Nguyen
- Cancer Research Laboratory, Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR 97331
| | - Brenna L. Stevens
- Cancer Research Laboratory, Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR 97331
| | - Daniel J. Elson
- Cancer Research Laboratory, Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR 97331
| | - Darren Finlay
- NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
| | - John Gamble
- Cancer Research Laboratory, Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR 97331
| | - Prasad Kopparapu
- Cancer Research Laboratory, Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR 97331
| | - Robyn L. Tanguay
- Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR 97331
- Linus Pauling Institute, Oregon State University, Corvallis, OR, USA
- The Pacific Northwest Center for Translational Environmental Health Research, Oregon State University, Corvallis, OR, 97331, USA
| | - Andrew B. Buermeyer
- Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR 97331
| | - Nancy I. Kerkvliet
- Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR 97331
| | - Siva K. Kolluri
- Cancer Research Laboratory, Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR 97331
- Linus Pauling Institute, Oregon State University, Corvallis, OR, USA
- The Pacific Northwest Center for Translational Environmental Health Research, Oregon State University, Corvallis, OR, 97331, USA
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Yoda T, Tochitani T, Usui T, Kouchi M, Inada H, Hosaka T, Kanno Y, Miyawaki I, Yoshinari K. Involvement of the CYP1A1 inhibition-mediated activation of aryl hydrocarbon receptor in drug-induced hepatotoxicity. J Toxicol Sci 2022; 47:359-373. [PMID: 36047110 DOI: 10.2131/jts.47.359] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Hepatotoxicity is one of the most common toxicities observed in non-clinical safety studies of drug candidates, and it is important to understand the hepatotoxicity mechanism to assess the risk of drug-induced liver injury in humans. In this study, we investigated the mechanism of hepatotoxicity caused by 2-[2-Methyl-1-(oxan-4-yl)-1H-benzimidazol-5-yl]-1,3-benzoxazole (DSP-0640), a drug candidate that showed hepatotoxicity characterized by centrilobular hypertrophy and vacuolation of hepatocytes in a 4-week oral repeated-dose toxicity study in male rats. In the liver of rats treated with DSP-0640, the expression of aryl hydrocarbon receptor (AHR) target genes, including Cyp1a1, was upregulated. In in vitro reporter assays, however, DSP-0640 showed only minimal AHR-activating potency. Therefore, we investigated the possibility that DSP-0640 indirectly activated AHR by inhibiting the CYP1 enzyme-dependent clearance of endogenous AHR agonists. In in vitro assays, DSP-0640 showed inhibitory effects on both rat and human CYP1A1 and enhanced rat and human AHR-mediated reporter gene expression induced by 6-formylindolo[3,2-b]carbazole, a well-known endogenous AHR agonist. The possible involvement of CYP1A1 inhibition in AHR activation was also demonstrated with other hepatotoxic compounds tacrine and albendazole. These results suggest that CYP1A1 inhibition-mediated AHR activation is involved in the hepatotoxicity caused by DSP-0640 and that DSP-0640 might induce hepatotoxicity in humans as well. We propose that CYP1A1 inhibition-mediated AHR activation is a novel mechanism for drug-induced hepatotoxicity.
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Affiliation(s)
- Tomomi Yoda
- Preclinical Research Unit, Sumitomo Pharma Co., Ltd.,Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka
| | | | - Toru Usui
- Preclinical Research Unit, Sumitomo Pharma Co., Ltd
| | - Mami Kouchi
- Preclinical Research Unit, Sumitomo Pharma Co., Ltd
| | | | - Takuomi Hosaka
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka
| | - Yuichiro Kanno
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka
| | | | - Kouichi Yoshinari
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka
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8
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Benoit L, Jornod F, Zgheib E, Tomkiewicz C, Koual M, Coustillet T, Barouki R, Audouze K, Vinken M, Coumoul X. Adverse outcome pathway from activation of the AhR to breast cancer-related death. ENVIRONMENT INTERNATIONAL 2022; 165:107323. [PMID: 35660951 DOI: 10.1016/j.envint.2022.107323] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/03/2022] [Accepted: 05/24/2022] [Indexed: 05/15/2023]
Abstract
Adverse outcome pathways (AOPs) are formalized and structured linear concepts that connect one molecular initiating event (MIE) to an adverse outcome (AO) via different key events (KE) through key event relationships (KER). They are mainly used in eco-toxicology toxicology, and regulatory health issues. AOPs must respond to specific guidelines from the Organization for Economic Co-operation and Development (OECD) to weight the evidence between each KE. Breast cancer is the deadliest cancer in women with a poor prognosis in case of metastatic breast cancer. The role of the environments in the formation of metastasis has been suggested. We hypothesized that activation of the AhR (MIE), a xenobiotic receptor, could lead to breast cancer related death (AO), through different KEs, constituting a new AOP. An artificial intelligence tool (AOP-helpfinder), which screens the available literature, was used to collect all existing scientific abstracts to build a novel AOP, using a list of key words. Four hundred and seven abstracts were found containing at least a word from our MIE list and either one word from our AO or KE list. A manual curation retained 113 pertinent articles, which were also screened using PubTator. From these analyses, an AOP was created linking the activation of the AhR to breast cancer related death through decreased apoptosis, inflammation, endothelial cell migration, angiogenesis, and invasion. These KEs promote an increased tumor growth, angiogenesis and migration which leads to breast cancer metastasis and breast cancer related death. The evidence of the proposed AOP was weighted using the tailored Bradford Hill criteria and the OECD guidelines. The confidence in our AOP was considered strong. An in vitro validation must be carried out, but our review proposes a strong relationship between AhR activation and breast cancer-related death with an innovative use of an artificial intelligence literature search.
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Affiliation(s)
- Louise Benoit
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France; Assistance Publique-Hôpitaux de Paris, European Hospital Georges-Pompidou, Gynecologic and Breast Oncologic Surgery Department, Paris, France.
| | - Florence Jornod
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France
| | - Elias Zgheib
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France
| | - Celine Tomkiewicz
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France
| | - Meriem Koual
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France; Assistance Publique-Hôpitaux de Paris, European Hospital Georges-Pompidou, Gynecologic and Breast Oncologic Surgery Department, Paris, France
| | - Thibaut Coustillet
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France
| | - Robert Barouki
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France; Assistance Publique-Hôpitaux de Paris, European Hospital Georges-Pompidou, Gynecologic and Breast Oncologic Surgery Department, Paris, France
| | - Karine Audouze
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France
| | - Mathieu Vinken
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Xavier Coumoul
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France
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Indole-3-Carbinol, a Phytochemical Aryl Hydrocarbon Receptor-Ligand, Induces the mRNA Overexpression of UBE2L3 and Cell Proliferation Arrest. Curr Issues Mol Biol 2022; 44:2054-2068. [PMID: 35678668 PMCID: PMC9164055 DOI: 10.3390/cimb44050139] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/28/2022] [Accepted: 05/05/2022] [Indexed: 11/17/2022] Open
Abstract
Cervical cancer (CC) is one of the most common cancers in women, and is linked to human papillomavirus (HPV) infection. The virus oncoprotein E6 binds to p53, resulting in its degradation and allowing uncontrolled cell proliferation. Meanwhile, the HPV E7 protein maintains host cell differentiation by targeting retinoblastoma tumor suppressor. The host cell can ubiquitinate E6 and E7 through UBE2L3, whose expression depends on the interaction between the aryl hydrocarbon receptor (AhR) with Xenobiotic Responsive Elements (XREs) located in the UBE2L3 gene promoter. In this study, we used cell culture to determine the effect of indole-3-carbinol (I3C) over cellular viability, apoptosis, cell proliferation, and mRNA levels of UBE2L3 and CYP1A1. In addition, patients’ samples were used to determine the mRNA levels of UBE2L3 and CYP1A1 genes. We found that I3C promotes the activation of AhR and decreases cell proliferation, possibly through UBE2L3 mRNA induction, which would result in the ubiquitination of HPV E7. Since there is a strong requirement for selective and cost-effective cancer treatments, natural AhR ligands such as I3C could represent a novel strategy for cancer treatment.
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Xie Y, Sun R, Gao L, Guan J, Wang J, Bell A, Zhu J, Zhang M, Xu M, Lu P, Cai X, Ren S, Xu P, Monga SP, Ma X, Yang D, Liu Y, Lu B, Xie W. Chronic Activation of LXRα Sensitizes Mice to Hepatocellular Carcinoma. Hepatol Commun 2022; 6:1123-1139. [PMID: 34981658 PMCID: PMC9035576 DOI: 10.1002/hep4.1880] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/27/2021] [Accepted: 11/18/2021] [Indexed: 01/26/2023] Open
Abstract
The oxysterol receptor liver X receptor (LXR) is a nuclear receptor best known for its function in the regulation of lipid and cholesterol metabolism. LXRs, both the α and β isoforms, have been suggested as potential therapeutic targets for several cancer types. However, there was a lack of report on whether and how LXRα plays a role in the development of hepatocellular carcinoma (HCC). In the current study, we found that systemic activation of LXRα in the VP-LXRα knock-in (LXRαKI) mice or hepatocyte-specific activation of LXRα in the VP-LXRα transgenic mice sensitized mice to liver tumorigenesis induced by the combined treatment of diethylnitrosamine (DEN) and 3,3',5,5'-tetrachloro-1,4-bis (pyridyloxy) benzene (TCPOBOP). Mechanistically, the LXRα-responsive up-regulation of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and the complement system, and down-regulation of bile acid metabolism, may have contributed to increased tumorigenesis. Accumulations of secondary bile acids and oxysterols were found in both the serum and liver tissue of LXRα activated mice. We also observed an induction of monocytic myeloid-derived suppressor cells accompanied by down-regulation of dendritic cells and cytotoxic T cells in DEN/TCPOBOP-induced liver tumors, indicating that chronic activation of LXRα may have led to the activation of innate immune suppression. The HCC sensitizing effect of LXRα activation was also observed in the c-MYC driven HCC model. Conclusion: Our results indicated that chronic activation of LXRα promotes HCC, at least in part, by promoting innate immune suppressor as a result of accumulation of oxysterols, as well as up-regulation of the IL-6/Janus kinase/STAT3 signaling and complement pathways.
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Affiliation(s)
- Yang Xie
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Runzi Sun
- Department of ImmunologyUniversity of PittsburghPittsburghPAUSA
| | - Li Gao
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
- Department of GastroenterologyPeking University People’s HospitalBeijingChina
| | - Jibin Guan
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Jingyuan Wang
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Aaron Bell
- Division of Experimental PathologyDepartment of PathologyUniversity of PittsburghPittsburghPAUSA
| | - Junjie Zhu
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Min Zhang
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Meishu Xu
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Peipei Lu
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Xinran Cai
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Songrong Ren
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Pengfei Xu
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Satdarshan P. Monga
- Division of Experimental PathologyDepartment of PathologyUniversity of PittsburghPittsburghPAUSA
- Pittsburgh Liver Research CenterUniversity of Pittsburgh Medical Center and University of Pittsburgh School of MedicinePittsburghPAUSA
| | - Xiaochao Ma
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Da Yang
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Yulan Liu
- Department of GastroenterologyPeking University People’s HospitalBeijingChina
| | - Binfeng Lu
- Department of ImmunologyUniversity of PittsburghPittsburghPAUSA
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
- Department of Pharmacology and Chemical BiologyUniversity of PittsburghPittsburghPAUSA
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11
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Tsuboi Y, Yamada H, Munetsuna E, Fujii R, Yamazaki M, Ando Y, Mizuno G, Hattori Y, Ishikawa H, Ohashi K, Hashimoto S, Hamajima N, Suzuki K. Increased risk of cancer mortality by smoking-induced aryl hydrocarbon receptor repressor DNA hypomethylation in Japanese population: A long-term cohort study. Cancer Epidemiol 2022; 78:102162. [PMID: 35461154 DOI: 10.1016/j.canep.2022.102162] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 04/07/2022] [Accepted: 04/12/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Smoking is well known to be a major risk factor for cancer, and to decrease the levels of aryl hydrocarbon receptor repressor (AHRR) DNA methylation. AHRR is a key regulator for AHR signaling, which is involved in chemical metabolism and cancer development. Therefore, smoking-induced AHRR DNA hypomethylation may be associated with cancer development. However, it has not been reported that association between AHHR DNA methylation and cancer mortality in Asian population. Hence, we examined whether AHRR DNA methylation levels were associated with cancer mortality in a Japanese population. METHODS This study was conducted with 812 participants (aged 38-80 years) who received a health check-up in 1990, and did not have a clinical histories. We followed up the participants until the end of 2019 (median: 27.8 years), and 100 participants died from cancer. The AHRR DNA methylation levels in peripheral blood mononuclear cells (PBMCs) were measured by the pyrosequencing method. We calculated the hazard ratio (HR) and 95% confidence interval (CI) for cancer mortality according to the baseline levels of AHRR DNA methylation. RESULTS We found that AHRR DNA hypomethylation was associated with a higher risk of all cancer mortality, especially smoking related cancers and lung cancer. (all cancer: HR, 1.28, 95% CI, 1.09-1.51; smoking-related cancers: HR, 1.35, 95% CI, 1.12-1.62; lung cancer: HR, 1.68, 95% CI, 1.24-2.26). CONCLUSIONS Smoking-induced AHRR DNA hypomethylation in PBMCs was associated with the risk of cancer mortality in Japanese population; therefore, hypomethylation of AHRR may be a useful biomarker of cancer mortality risk.
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Affiliation(s)
- Yoshiki Tsuboi
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, Toyoake, Aichi 470-1192, Japan.
| | - Hiroya Yamada
- Department of Hygiene, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.
| | - Eiji Munetsuna
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.
| | - Ryosuke Fujii
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, Toyoake, Aichi 470-1192, Japan.
| | - Mirai Yamazaki
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa 761-0123, Japan.
| | - Yoshitaka Ando
- Department of Informative Clinical Medicine, Fujita Health University School of Medical Sciences, Toyoake, Aichi 470-1192, Japan.
| | - Genki Mizuno
- Department of Informative Clinical Medicine, Fujita Health University School of Medical Sciences, Toyoake, Aichi 470-1192, Japan.
| | - Yuji Hattori
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, Toyoake, Aichi 470-1192, Japan.
| | - Hiroaki Ishikawa
- Department of Informative Clinical Medicine, Fujita Health University School of Medical Sciences, Toyoake, Aichi 470-1192, Japan.
| | - Koji Ohashi
- Department of Informative Clinical Medicine, Fujita Health University School of Medical Sciences, Toyoake, Aichi 470-1192, Japan.
| | - Shuji Hashimoto
- Department of Hygiene, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.
| | - Nobuyuki Hamajima
- Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
| | - Koji Suzuki
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, Toyoake, Aichi 470-1192, Japan.
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12
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Ceci R, Diletti G, Bellocci M, Chiumiento F, D'Antonio S, De Benedictis A, Leva M, Pirito L, Scortichini G, Fernandes AR. Brominated and chlorinated contaminants in food (PCDD/Fs, PCBs, PBDD/Fs PBDEs): Simultaneous determination and occurrence in Italian produce. CHEMOSPHERE 2022; 288:132445. [PMID: 34626655 DOI: 10.1016/j.chemosphere.2021.132445] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 09/21/2021] [Accepted: 09/30/2021] [Indexed: 06/13/2023]
Abstract
Validated methodology for the simultaneous determination of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) and polybrominated diphenyl ethers (PBDEs) in foods of animal origin is presented. Method performance indicators were equivalent or better than those required for the control of EU regulated (EU, 2017/644) PCDD/F and PCB congeners in these foods, and for risk assessment through dietary intake. The method uses a high (>90%) proportion of 13Carbon-labelled surrogates for internal standardisation combined with high resolution mass spectrometry that allow accurate quantitation, and this was confirmed by multiple successful participations in proficiency testing for PCDD/Fs, PCBs and PBDEs in food. The same validation and method performance requirements as used for PCDD/Fs were followed for PBDD/Fs. The analysis of a range of food samples (eggs, milk, fish, shellfish, pork, beef and poultry), showed the occurrence of all four classes of contaminants at varying concentration ranges. In general, PCBs were the most prominent contaminant, both, in terms of dioxin-like toxicity, as well as in the occurrence of non-dioxin-like congeners, an observation that concurs with those made in other studies on Italian foods. The levels of PCDD/F and PCB occurrence are consistent with a gradual decline in contamination as reported by some other similar studies. Although all the determined contaminants were detected in the sampled foods, there was poor correlation between the occurrences of the brominated and chlorinated contaminants, and between PBDEs and PBDD/Fs, but better associations were observed between the occurrences of the chlorinated contaminants.
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Affiliation(s)
- Roberta Ceci
- Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise G. Caporale, Via Campo Boario, 64100, Teramo, Italy
| | - Gianfranco Diletti
- Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise G. Caporale, Via Campo Boario, 64100, Teramo, Italy
| | - Mirella Bellocci
- Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise G. Caporale, Via Campo Boario, 64100, Teramo, Italy
| | - Francesco Chiumiento
- Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise G. Caporale, Via Campo Boario, 64100, Teramo, Italy
| | - Silvia D'Antonio
- Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise G. Caporale, Via Campo Boario, 64100, Teramo, Italy
| | - Alfonso De Benedictis
- Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise G. Caporale, Via Campo Boario, 64100, Teramo, Italy
| | - Manuela Leva
- Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise G. Caporale, Via Campo Boario, 64100, Teramo, Italy
| | - Luigi Pirito
- Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise G. Caporale, Via Campo Boario, 64100, Teramo, Italy
| | - Giampiero Scortichini
- Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise G. Caporale, Via Campo Boario, 64100, Teramo, Italy
| | - Alwyn R Fernandes
- School of Environmental Sciences, University of East Anglia, Norwich, NR4 7TJ, UK.
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13
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Sahebnasagh A, Hashemi J, Khoshi A, Saghafi F, Avan R, Faramarzi F, Azimi S, Habtemariam S, Sureda A, Khayatkashani M, Safdari M, Rezai Ghaleno H, Soltani H, Khayat Kashani HR. Aromatic hydrocarbon receptors in mitochondrial biogenesis and function. Mitochondrion 2021; 61:85-101. [PMID: 34600156 DOI: 10.1016/j.mito.2021.09.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 09/17/2021] [Accepted: 09/27/2021] [Indexed: 12/11/2022]
Abstract
Mitochondria are ubiquitous membrane-bound organelles that not only play a key role in maintaining cellular energy homeostasis and metabolism but also in signaling and apoptosis. Aryl hydrocarbons receptors (AhRs) are ligand-activated transcription factors that recognize a wide variety of xenobiotics, including polyaromatic hydrocarbons and dioxins, and activate diverse detoxification pathways. These receptors are also activated by natural dietary compounds and endogenous metabolites. In addition, AhRs can modulate the expression of a diverse array of genes related to mitochondrial biogenesis and function. The aim of the present review is to analyze scientific data available on the AhR signaling pathway and its interaction with the intracellular signaling pathways involved in mitochondrial functions, especially those related to cell cycle progression and apoptosis. Various evidence have reported the crosstalk between the AhR signaling pathway and the nuclear factor κB (NF-κB), tyrosine kinase receptor signaling and mitogen-activated protein kinases (MAPKs). The AhR signaling pathway seems to promote cell cycle progression in the absence of exogenous ligands, whereas the presence of exogenous ligands induces cell cycle arrest. However, its effects on apoptosis are controversial since activation or overexpression of AhR has been observed to induce or inhibit apoptosis depending on the cell type. Regarding the mitochondria, although activation by endogenous ligands is related to mitochondrial dysfunction, the effects of endogenous ligands are not well understood but point towards antiapoptotic effects and inducers of mitochondrial biogenesis.
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Affiliation(s)
- Adeleh Sahebnasagh
- Clinical Research Center, Department of Internal Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Javad Hashemi
- Department of Pathobiology and Laboratory Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Amirhosein Khoshi
- Department of Clinical Biochemistry, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Fatemeh Saghafi
- Department of Clinical Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Razieh Avan
- Assistant Professor of Clinical Pharmacy, Department of Clinical Pharmacy, Medical Toxicology and Drug Abuse Research Center (MTDRC), Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Fatemeh Faramarzi
- Clinical Pharmacy Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Saeed Azimi
- Student Research Committee, Department of Clinical Pharmacy, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Solomon Habtemariam
- Pharmacognosy Research Laboratories and Herbal Analysis Services, School of Science, University of Greenwich, Central Avenue, Chatham-Maritime, Kent ME4 4TB, United Kingdom
| | - Antoni Sureda
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands and Health Research Institute of Balearic Islands (IdISBa), Palma de Mallorca, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Maryam Khayatkashani
- School of Iranian Traditional Medicine, Tehran University of Medical Sciences, 14155-6559 Tehran, Iran
| | - Mohammadreza Safdari
- Department of Orthopedic Surgery, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Hassan Rezai Ghaleno
- Department of Surgery, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Hosseinali Soltani
- Department of General Surgery, Imam Ali Hospital, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Hamid Reza Khayat Kashani
- Department of Neurosurgery, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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14
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Oesch F, Fruth D, Hengstler JG, Fabian E, Berger FI, Landsiedel R. Enigmatic mechanism of the N-vinylpyrrolidone hepatocarcinogenicity in the rat. Arch Toxicol 2021; 95:3717-3744. [PMID: 34595563 PMCID: PMC8536644 DOI: 10.1007/s00204-021-03151-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 08/26/2021] [Indexed: 11/24/2022]
Abstract
N-vinyl pyrrolidone (NVP) is produced up to several thousand tons per year as starting material for the production of polymers to be used in pharmaceutics, cosmetics and food technology. Upon inhalation NVP was carcinogenic in the rat, liver tumor formation is starting already at the rather low concentration of 5 ppm. Hence, differentiation whether NVP is a genotoxic carcinogen (presumed to generally have no dose threshold for the carcinogenic activity) or a non-genotoxic carcinogen (with a potentially definable threshold) is highly important. In the present study, therefore, the existing genotoxicity investigations on NVP (all showing consistently negative results) were extended and complemented with investigations on possible alternative mechanisms, which also all proved negative. All tests were performed in the same species (rat) using the same route of exposure (inhalation) and the same doses of NVP (5, 10 and 20 ppm) as had been used in the positive carcinogenicity test. Specifically, the tests included an ex vivo Comet assay (so far not available) and an ex vivo micronucleus test (in contrast to the already available micronucleus test in mice here in the same species and by the same route of application as in the bioassay which had shown the carcinogenicity), tests on oxidative stress (non-protein-bound sulfhydryls and glutathione recycling test), mechanisms mediated by hepatic receptors, the activation of which had been shown earlier to lead to carcinogenicity in some instances (Ah receptor, CAR, PXR, PPARα). No indications were obtained for any of the investigated mechanisms to be responsible for or to contribute to the observed carcinogenicity of NVP. The most important of these exclusions is genotoxicity. Thus, NVP can rightfully be regarded and treated as a non-genotoxic carcinogen and threshold approaches to the assessment of this chemical are supported. However, the mechanism underlying the carcinogenicity of NVP in rats remains unclear.
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Affiliation(s)
- Franz Oesch
- Oesch-Tox Toxicological Consulting and Expert Opinions GmbH&CoKG, Rheinblick 21, 55263, Ingelheim, Germany.,Institute of Toxicology, Johannes Gutenberg University, 55131, Mainz, Germany
| | - Daniela Fruth
- Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany.,Knoell Germany GmbH, Eastsite XII, Konrad-Zuse-Ring 25, 68163, Mannheim, Germany
| | - Jan G Hengstler
- Leibniz Research Centre for Working Environment and Human Factors (IfADo), University of Dortmund, Dortmund, Germany
| | - Eric Fabian
- Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany
| | - Franz Ingo Berger
- Regulatory Toxicology Chemicals, BASF SE, 67056, Ludwigshafen am Rhein, Germany
| | - Robert Landsiedel
- Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany.
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15
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Chen F, Xu G, Tian W, Gou S. Breakdown of chemo-immune resistance by a TDO2-targeted Pt(IV) prodrug via attenuating endogenous Kyn-AhR-AQP4 metabolic circuity and TLS-promoted genomic instability. Biochem Pharmacol 2021; 193:114785. [PMID: 34562469 DOI: 10.1016/j.bcp.2021.114785] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 09/14/2021] [Accepted: 09/20/2021] [Indexed: 11/16/2022]
Abstract
A tryptophan-2,3-dioxygenase 2 (TDO2)-targeted Pt(IV) prodrug, DN604-TDOi, was designed to prove that the multi-action compound could overcome drug resistance and relieve immunosuppression via introducing a TDO2 inhibitor to the axial position of a six-coordinate Pt(IV) hybrid. Several in vitro biological studies on cisplatin-resistant NSCLC cancer cells suggested that TDO2-targeted Pt(IV) prodrug could combat cisplatin resistance via influencing TDO2-kynurenine (Kyn)-aryl hydrocarbon receptor (AhR)-Aquaporin-4 (AQP4) metabolic circuity and AhR-human DNA polymerase (hpol) κ-induced translesion DNA synthesis (TLS) genomic instability, which are positive in drug-resistant human tumors associated with malignant progression and poor survival. Remarkably, we observed that DN604-TDOi could inhibit TDO2-mediated constitutive Kyn-AhR-AQP4 signaling pathway and suppress hpol κ expression, leading to potential decrease of cell motility and genomic instability in A549/cDDP cells. It was confirmed that TDO2-targeted Pt(IV) prodrug could harness Kyn-AhR-AQP4 metabolic circuitry and TLS genomic instability, exerting antitumor effects in C57BL6 but not TDO2-/- mice. Moreover, the Pt(IV) prodrug improved the intratumoral infiltration of Teff cells and reduced the recruitment of Treg cells. The results provided compelling preclinical evidence that TDO2-targeted Pt(IV) prodrug could abrogate immune chemotherapeutic resistance via decaying TDO2-mediated Kyn-AhR-AQP4 immunosuppression and AhR-hpol κ-induced TLS genomic instability, underscoring the development of a novel Pt(IV)-based candidate as a potent immunotherapeutic agent for chemo-immune resistance prevention.
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Affiliation(s)
- Feihong Chen
- Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China
| | - Gang Xu
- Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China
| | - Wenyuan Tian
- Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China
| | - Shaohua Gou
- Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
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16
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Larigot L, Benoit L, Koual M, Tomkiewicz C, Barouki R, Coumoul X. Aryl Hydrocarbon Receptor and Its Diverse Ligands and Functions: An Exposome Receptor. Annu Rev Pharmacol Toxicol 2021; 62:383-404. [PMID: 34499523 DOI: 10.1146/annurev-pharmtox-052220-115707] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The aryl hydrocarbon receptor (AhR) is a transcriptional factor that regulates multiple functions following its activation by a variety of ligands, including xenobiotics, natural products, microbiome metabolites, and endogenous molecules. Because of this diversity, the AhR constitutes an exposome receptor. One of its main functions is to regulate several lines of defense against chemical insults and bacterial infections. Indeed, in addition to its well-established detoxication function, it has several functions at physiological barriers, and it plays a critical role in immunomodulation. The AhR is also involved in the development of several organs and their homeostatic maintenance. Its activity depends on the type of ligand and on the time frame of the receptor activation, which can be either sustained or transient, leading in some cases to opposite modes of regulations as illustrated in the regulation of different cancer pathways. The development of selective modulators and their pharmacological characterization are important areas of research. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Lucie Larigot
- INSERM UMR-S1124, T3S, Toxicologie Environnementale, Cibles thérapeutiques, Signalisation cellulaire et Biomarqueurs, and Université de Paris, 75006 Paris, France;
| | - Louise Benoit
- INSERM UMR-S1124, T3S, Toxicologie Environnementale, Cibles thérapeutiques, Signalisation cellulaire et Biomarqueurs, and Université de Paris, 75006 Paris, France; .,Service de Chirurgie Cancérologique Gynécologique et du Sein, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, 75015 Paris, France
| | - Meriem Koual
- INSERM UMR-S1124, T3S, Toxicologie Environnementale, Cibles thérapeutiques, Signalisation cellulaire et Biomarqueurs, and Université de Paris, 75006 Paris, France; .,Service de Chirurgie Cancérologique Gynécologique et du Sein, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, 75015 Paris, France
| | - Céline Tomkiewicz
- INSERM UMR-S1124, T3S, Toxicologie Environnementale, Cibles thérapeutiques, Signalisation cellulaire et Biomarqueurs, and Université de Paris, 75006 Paris, France;
| | - Robert Barouki
- INSERM UMR-S1124, T3S, Toxicologie Environnementale, Cibles thérapeutiques, Signalisation cellulaire et Biomarqueurs, and Université de Paris, 75006 Paris, France; .,Service de Chirurgie Cancérologique Gynécologique et du Sein, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, 75015 Paris, France
| | - Xavier Coumoul
- INSERM UMR-S1124, T3S, Toxicologie Environnementale, Cibles thérapeutiques, Signalisation cellulaire et Biomarqueurs, and Université de Paris, 75006 Paris, France;
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17
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Abstract
The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that is a member of the PER-ARNT-SIM superfamily of environmental sensors. This receptor has been a molecule of interest for many years in the field of toxicology, as it was originally discovered to mediate the toxic effects of certain environmental pollutants like benzo(a)pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. While all animals express this protein, there is naturally occurring variability in receptor size and responsiveness to ligand. This naturally occurring variation, particularly in mice, has been an essential tool in the discovery and early characterization of the AHR. Genetic models including congenic mice and induced mutations at the Ahr locus have proven invaluable in further understanding the role of the AHR in adaptive metabolism and TCDD-induced toxicity. The creation and examination of Ahr null mice revealed an important physiological role for the AHR in vascular and hepatic development and mediation of the immune system. In this review, we attempt to provide an overview to many of the AHR models that have aided in the understanding of AHR biology thus far. We describe the naturally occurring polymorphisms, congenic models, induced mutations at the Ahr locus and at the binding partner Ah Receptor Nuclear Translocator and chaperone, Ah receptor associated 9 loci in mice, with a brief description of naturally occurring and induced mutations in rats.
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Affiliation(s)
- Rachel H Wilson
- Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, WI, USA.,Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Christopher A Bradfield
- Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, WI, USA.,Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.,Biotechnology Center, University of Wisconsin, Madison, WI, USA
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18
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Stockinger B, Shah K, Wincent E. AHR in the intestinal microenvironment: safeguarding barrier function. Nat Rev Gastroenterol Hepatol 2021; 18:559-570. [PMID: 33742166 PMCID: PMC7611426 DOI: 10.1038/s41575-021-00430-8] [Citation(s) in RCA: 192] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/09/2021] [Indexed: 02/01/2023]
Abstract
Mammalian aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that belongs to the basic helix-loop-helix (bHLH)-PAS family of transcription factors, which are evolutionarily conserved environmental sensors. In the absence of ligands, AHR resides in the cytoplasm in a complex with molecular chaperones such as HSP90, XAP2 and p23. Upon ligand binding, AHR translocates into the nuclear compartment, where it dimerizes with its partner protein, AHR nuclear translocator (ARNT), an obligatory partner for the DNA-binding and functional activity. Historically, AHR had mostly been considered as a key intermediary for the detrimental effects of environmental pollutants on the body. However, following the discovery of AHR-mediated functions in various immune cells, as well as the emergence of non-toxic 'natural' AHR ligands, this view slowly began to change, and the study of AHR-deficient mice revealed a plethora of important beneficial functions linked to AHR activation. This Review focuses on regulation of the AHR pathway and the barrier-protective roles AHR has in haematopoietic, as well as non-haematopoietic, cells within the intestinal microenvironment. It covers the nature of AHR ligands and feedback regulation of the AHR pathway, outlining the currently known physiological functions in immune, epithelial, endothelial and neuronal cells of the intestine.
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Affiliation(s)
| | | | - Emma Wincent
- Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
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19
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Mony V, Nirmal RM, Parvathi V, Parvathy RL, Varun BR, Jayanthi P. Evaluation of aryl hydrocarbon receptor expression in oral squamous cell carcinoma and normal oral mucosa using western blot. J Oral Maxillofac Pathol 2021; 25:68-73. [PMID: 34349414 PMCID: PMC8272475 DOI: 10.4103/jomfp.jomfp_287_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/10/2020] [Accepted: 09/22/2020] [Indexed: 11/04/2022] Open
Abstract
Background Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that acts as a binding site for toxic chemicals, particularly the dioxin group of chemicals. Elevated levels of AHR have been observed in various human cancers, including lung carcinomas, hepatic carcinomas and in mammary tumors. However, the expression of AHR in oral squamous cell carcinoma (OSCC) patients who are tobacco users are less explored. Aims and Objectives The aim of the present study is to evaluate and compare AHR levels in OSSC patients and in normals using Western blot technique in an attempt to explore the possible role of AHR in oral carcinogenesis. Materials and Methods The study sample consisted of ten oral squamous cell carcinoma cases which were diagnosed clinically and confirmed histopathologically as OSCC and four samples of the normal oral mucosa. AHR protein expression was evaluated using Western blot technique and chemiluminescence detection kit. The densitometry was performed on a Microtek scan maker MSP flatbed scanner and quantified using Image J software. Mean AHR protein levels were calculated and compared between OSCC and normal oral mucosa using Student's t-test. Results The mean AHR protein level in OSCC samples (n = 10) was 2878.90 ± 1231.27 and 975.75 ± 227.27 in the normal oral mucosa (n = 4). The OSCC samples showed significantly higher levels of AHR protein compared to the normal oral mucosa (P = 0.008). Conclusion The study showed a significantly higher expression of AHR in oral squamous cell carcinoma samples when compared to the normal oral mucosa, suggesting a possible role of AHR in the initiation, promotion and progression of oral squamous cell carcinoma.
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Affiliation(s)
- Vinod Mony
- Department of Oral and Maxillofacial Pathology, PMS College of Dental Sciences and Research, Thiruvananthapuram, Kerala, India
| | - R Madhavan Nirmal
- Department of Oral and Maxillofacial Pathology, Rajah Muthiah Dental College and Hospital, Annamalai University, Chidambaram, Tamil Nadu, India
| | - V Parvathi
- Department of Oral and Maxillofacial Pathology, Rajah Muthiah Dental College and Hospital, Annamalai University, Chidambaram, Tamil Nadu, India
| | - R L Parvathy
- Department of Pharmacology, PMS College of Dental Sciences and Research, Thiruvananthapuram, Kerala, India
| | - B R Varun
- Department of Oral and Maxillofacial Pathology, PMS College of Dental Sciences and Research, Thiruvananthapuram, Kerala, India
| | - P Jayanthi
- Department of Oral and Maxillofacial Pathology, Azeezia College of Dental Sciences and Research, Kollam, Kerala, India
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20
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Wang Z, Snyder M, Kenison JE, Yang K, Lara B, Lydell E, Bennani K, Novikov O, Federico A, Monti S, Sherr DH. How the AHR Became Important in Cancer: The Role of Chronically Active AHR in Cancer Aggression. Int J Mol Sci 2020; 22:ijms22010387. [PMID: 33396563 PMCID: PMC7795223 DOI: 10.3390/ijms22010387] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 12/25/2020] [Accepted: 12/28/2020] [Indexed: 12/13/2022] Open
Abstract
For decades, the aryl hydrocarbon receptor (AHR) was studied for its role in environmental chemical toxicity i.e., as a quirk of nature and a mediator of unintended consequences of human pollution. During that period, it was not certain that the AHR had a “normal” physiological function. However, the ongoing accumulation of data from an ever-expanding variety of studies on cancer, cancer immunity, autoimmunity, organ development, and other areas bears witness to a staggering array of AHR-controlled normal and pathological activities. The objective of this review is to discuss how the AHR has gone from a likely contributor to genotoxic environmental carcinogen-induced cancer to a master regulator of malignant cell progression and cancer aggression. Particular focus is placed on the association between AHR activity and poor cancer outcomes, feedback loops that control chronic AHR activity in cancer, and the role of chronically active AHR in driving cancer cell invasion, migration, cancer stem cell characteristics, and survival.
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Affiliation(s)
- Zhongyan Wang
- Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA; (Z.W.); (K.Y.); (E.L.)
| | - Megan Snyder
- Graduate Program in Genetics and Genomics, Division of Graduate Medical Sciences, Boston University School of Medicine, Boston, MA 02118, USA;
| | - Jessica E. Kenison
- Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA;
| | - Kangkang Yang
- Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA; (Z.W.); (K.Y.); (E.L.)
| | - Brian Lara
- Department of Environmental Health, Boston University, Boston, MA 02118, USA; (B.L.); (K.B.)
| | - Emily Lydell
- Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA; (Z.W.); (K.Y.); (E.L.)
| | - Kawtar Bennani
- Department of Environmental Health, Boston University, Boston, MA 02118, USA; (B.L.); (K.B.)
| | | | - Anthony Federico
- Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; (A.F.); (S.M.)
| | - Stefano Monti
- Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; (A.F.); (S.M.)
| | - David H. Sherr
- Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA; (Z.W.); (K.Y.); (E.L.)
- Correspondence: ; Tel.: +1-617-358-1707
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21
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Pirzadeh M, Khalili N, Rezaei N. The interplay between aryl hydrocarbon receptor, H. pylori, tryptophan, and arginine in the pathogenesis of gastric cancer. Int Rev Immunol 2020; 41:299-312. [DOI: 10.1080/08830185.2020.1851371] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Marzieh Pirzadeh
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Nastaran Khalili
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Sheffield, UK
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22
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Koual M, Tomkiewicz C, Cano-Sancho G, Antignac JP, Bats AS, Coumoul X. Environmental chemicals, breast cancer progression and drug resistance. Environ Health 2020; 19:117. [PMID: 33203443 PMCID: PMC7672852 DOI: 10.1186/s12940-020-00670-2] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 10/21/2020] [Indexed: 05/04/2023]
Abstract
Breast cancer (BC) is one of the most common causes of cancer in the world and the second leading cause of cancer deaths among women. Mortality is associated mainly with the development of metastases. Identification of the mechanisms involved in metastasis formation is, therefore, a major public health issue. Among the proposed risk factors, chemical environment and pollution are increasingly suggested to have an effect on the signaling pathways involved in metastatic tumor cells emergence and progression. The purpose of this article is to summarize current knowledge about the role of environmental chemicals in breast cancer progression, metastasis formation and resistance to chemotherapy. Through a scoping review, we highlight the effects of a wide variety of environmental toxicants, including persistent organic pollutants and endocrine disruptors, on invasion mechanisms and metastatic processes in BC. We identified the epithelial-to-mesenchymal transition and cancer-stemness (the stem cell-like phenotype in tumors), two mechanisms suspected of playing key roles in the development of metastases and linked to chemoresistance, as potential targets of contaminants. We discuss then the recently described pro-migratory and pro-invasive Ah receptor signaling pathway and conclude that his role in BC progression is still controversial. In conclusion, although several pertinent pathways for the effects of xenobiotics have been identified, the mechanisms of actions for multiple other molecules remain to be established. The integral role of xenobiotics in the exposome in BC needs to be further explored through additional relevant epidemiological studies that can be extended to molecular mechanisms.
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Affiliation(s)
- Meriem Koual
- INSERM UMR-S1124, 3TS, Toxicologie Pharmacologie et Signalisation Cellulaire, Université de Paris, Paris, France.
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Service de Chirurgie Cancérologique Gynécologique et du Sein, Paris, France.
- Faculté de Médecine, Université de Paris, Paris, France.
| | - Céline Tomkiewicz
- INSERM UMR-S1124, 3TS, Toxicologie Pharmacologie et Signalisation Cellulaire, Université de Paris, Paris, France
- Faculté de Médecine, Université de Paris, Paris, France
| | | | | | - Anne-Sophie Bats
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Service de Chirurgie Cancérologique Gynécologique et du Sein, Paris, France
- Faculté de Médecine, Université de Paris, Paris, France
- INSERM UMR-S1147, Equipe labellisée Ligue Nationale Contre le Cancer, Université de Paris, Paris, France
| | - Xavier Coumoul
- INSERM UMR-S1124, 3TS, Toxicologie Pharmacologie et Signalisation Cellulaire, Université de Paris, Paris, France.
- Faculté de Médecine, Université de Paris, Paris, France.
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23
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Shi MJ, Meng XY, Fontugne J, Chen CL, Radvanyi F, Bernard-Pierrot I. Identification of new driver and passenger mutations within APOBEC-induced hotspot mutations in bladder cancer. Genome Med 2020; 12:85. [PMID: 32988402 PMCID: PMC7646471 DOI: 10.1186/s13073-020-00781-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 09/11/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND APOBEC-driven mutagenesis and functional positive selection of mutated genes may synergistically drive the higher frequency of some hotspot driver mutations compared to other mutations within the same gene, as we reported for FGFR3 S249C. Only a few APOBEC-associated driver hotspot mutations have been identified in bladder cancer (BCa). Here, we systematically looked for and characterised APOBEC-associated hotspots in BCa. METHODS We analysed 602 published exome-sequenced BCas, for part of which gene expression data were also available. APOBEC-associated hotspots were identified by motif-mapping, mutation signature fitting and APOBEC-mediated mutagenesis comparison. Joint analysis of DNA hairpin stability and gene expression was performed to predict driver or passenger hotspots. Aryl hydrocarbon receptor (AhR) activity was calculated based on its target genes expression. Effects of AhR knockout/inhibition on BCa cell viability were analysed. RESULTS We established a panel of 44 APOBEC-associated hotspot mutations in BCa, which accounted for about half of the hotspot mutations. Fourteen of them overlapped with the hotspots found in other cancer types with high APOBEC activity. They mostly occurred in the DNA lagging-strand templates and the loop of DNA hairpins. APOBEC-associated hotspots presented systematically a higher prevalence than the other mutations within each APOBEC-target gene, independently of their functional impact. A combined analysis of DNA loop stability and gene expression allowed to distinguish known passenger from known driver hotspot mutations in BCa, including loss-of-function mutations affecting tumour suppressor genes, and to predict new candidate drivers, such as AHR Q383H. We further characterised AHR Q383H as an activating driver mutation associated with high AhR activity in luminal tumours. High AhR activity was also found in tumours presenting amplifications of AHR and its co-receptor ARNT. We finally showed that BCa cells presenting those different genetic alterations were sensitive to AhR inhibition. CONCLUSIONS Our study identified novel potential drivers within APOBEC-associated hotspot mutations in BCa reinforcing the importance of APOBEC mutagenesis in BCa. It could allow a better understanding of BCa biology and aetiology and have clinical implications such as AhR as a potential therapeutic target. Our results also challenge the dogma that all hotspot mutations are drivers and mostly gain-of-function mutations affecting oncogenes.
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Affiliation(s)
- Ming-Jun Shi
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Institut Curie, CNRS, UMR144, Molecular Oncology team, PSL Research University, 26 Rue d'Ulm, 75005, Paris, France
- Paris-Saclay University, Paris, France
| | - Xiang-Yu Meng
- Institut Curie, CNRS, UMR144, Molecular Oncology team, PSL Research University, 26 Rue d'Ulm, 75005, Paris, France.
- Paris-Saclay University, Paris, France.
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
| | - Jacqueline Fontugne
- Institut Curie, CNRS, UMR144, Molecular Oncology team, PSL Research University, 26 Rue d'Ulm, 75005, Paris, France
- Paris-Saclay University, Paris, France
| | - Chun-Long Chen
- Institut Curie, CNRS, UMR3244, PSL Research University, Paris, France
- Sorbonne Université, Paris, France
| | - François Radvanyi
- Institut Curie, CNRS, UMR144, Molecular Oncology team, PSL Research University, 26 Rue d'Ulm, 75005, Paris, France
| | - Isabelle Bernard-Pierrot
- Institut Curie, CNRS, UMR144, Molecular Oncology team, PSL Research University, 26 Rue d'Ulm, 75005, Paris, France.
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24
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Mengoni M, Braun AD, Gaffal E, Tüting T. The aryl hydrocarbon receptor promotes inflammation-induced dedifferentiation and systemic metastatic spread of melanoma cells. Int J Cancer 2020; 147:2902-2913. [PMID: 32790916 DOI: 10.1002/ijc.33252] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 06/21/2020] [Accepted: 07/24/2020] [Indexed: 12/15/2022]
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand binding-transcription factor of the basic helix-loop-helix family regulating multiple cellular functions such as differentiation, cell cycle, apoptosis, and inflammatory reactions. In neoplastic diseases, the AHR has been described to modulate proliferation and differentiation in dichotomous ways, either inhibiting or augmenting the growth of tumors. The precise role of AHR in melanoma is mostly unknown. Here, we report a functional effect of AHR activation on inflammation-induced melanoma cell dedifferentiation and the development of lung metastases in a mouse model. Via in silico analyses of "The Cancer Genome Atlas" human melanoma cohort, we detected a correlation between AHR expression levels and a dedifferentiated melanoma cell phenotype with an invasive gene signature, which we were able to functionally recapitulate in a panel of human melanoma cell lines. Both human and mouse melanoma cell lines upregulated AHR expression after inflammatory stimulation with tumor necrosis factor-α (TNF-α). Activation of AHR in human and mouse melanoma cell lines with the endogenous ligand formylindolo(3,2-b)carbazole (FICZ) promoted inflammation-induced dedifferentiation in vitro. Importantly, mouse melanoma cells with CRISPR/Cas9-mediated disruption of the AHR gene showed impaired in vivo tumor growth after transplantation in the skin as well as decreased numbers of spontaneous lung metastases. Taken together, our results demonstrate a functional role for AHR expression in melanoma development and metastatic progression. This provides a scientific basis for future experiments that further dissect the underlying molecular mechanisms and assess the potential for AHR inhibition as part of multimodal melanoma treatment strategies.
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Affiliation(s)
- Miriam Mengoni
- Laboratory for Experimental Dermatology, Department of Dermatology, University Hospital Magdeburg, Magdeburg, Germany
| | - Andreas Dominik Braun
- Laboratory for Experimental Dermatology, Department of Dermatology, University Hospital Magdeburg, Magdeburg, Germany
| | - Evelyn Gaffal
- Laboratory for Experimental Dermatology, Department of Dermatology, University Hospital Magdeburg, Magdeburg, Germany
| | - Thomas Tüting
- Laboratory for Experimental Dermatology, Department of Dermatology, University Hospital Magdeburg, Magdeburg, Germany
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25
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Lu P, Cai X, Guo Y, Xu M, Tian J, Locker J, Xie W. Constitutive Activation of the Human Aryl Hydrocarbon Receptor in Mice Promotes Hepatocarcinogenesis Independent of Its Coactivator Gadd45b. Toxicol Sci 2020; 167:581-592. [PMID: 30346592 DOI: 10.1093/toxsci/kfy263] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or dioxin, is a potent liver cancer promoter through its sustained activation of the aryl hydrocarbon receptor (Ahr) in rodents. However, the carcinogenic effect of TCDD and AHR in humans has been controversial. It has been suggested that the inter-species difference in the carcinogenic activity of AhR is largely due to different ligand affinity in that TCDD has a 10-fold lower affinity for the human AHR compared with the mouse Ahr. It remains unclear whether the activation of human AHR is sufficient to promote hepatocellular carcinogenesis. The goal of this study is to clarify whether activation of human AHR can promote hepatocarcinogenesis. Here we reported the oncogenic activity of human AHR in promoting hepatocellular carcinogenesis. Constitutive activation of the human AHR in transgenic mice was as efficient as its mouse counterpart in promoting diethylnitrosamine (DEN)-initiated hepatocellular carcinogenesis. The growth arrest and DNA damage-inducible gene 45 β (Gadd45b), a signaling molecule inducible by external stress and UV irradiation, is highly induced upon AHR activation. Further analysis revealed that Gadd45b is a novel AHR target gene and a transcriptional coactivator of AHR. Interestingly, ablation of Gadd45b in mice did not abolish the tumor promoting effects of the human AHR. Collectively, our findings suggested that constitutive activation of human AHR was sufficient to promote hepatocarcinogenesis.
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Affiliation(s)
- Peipei Lu
- Center for Pharmacogenetics.,Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
| | - Xinran Cai
- Center for Pharmacogenetics.,Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
| | - Yan Guo
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 200025
| | - Meishu Xu
- Center for Pharmacogenetics.,Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
| | | | | | - Wen Xie
- Center for Pharmacogenetics.,Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261.,Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
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26
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Zhou G. Tobacco, air pollution, environmental carcinogenesis, and thoughts on conquering strategies of lung cancer. Cancer Biol Med 2019; 16:700-713. [PMID: 31908889 PMCID: PMC6936241 DOI: 10.20892/j.issn.2095-3941.2019.0180] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 07/08/2019] [Indexed: 12/15/2022] Open
Abstract
Each year there will be an estimated 2.1 million new lung cancer cases and 1.8 million lung cancer deaths worldwide. Tobacco smoke is the No.1 risk factors of lung cancer, accounting for > 85% lung cancer deaths. Air pollution, or haze, comprises ambient air pollution and household air pollution, which are reported to cause 252,000 and 304,000 lung cancer deaths each year, respectively. Tobacco smoke and haze (hereafter, smohaze) contain fine particles originated from insufficient combustion of biomass or coal, have quite similar carcinogens, and cause similar diseases. Smohaze exert hazardous effects on exposed populations, including induction of a large amount of mutations in the genome, alternative splicing of mRNAs, abnormalities in epigenomics, initiation of tumor-promoting chronic inflammation, and facilitating immune escape of transformed cells. Tackling smohaze and development of multi-targets-based preventive and therapeutic approaches targeting smohaze-induced carcinogenesis are the key to conquer lung cancer in the future.
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Affiliation(s)
- Guangbiao Zhou
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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27
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Wu PY, Yu IS, Lin YC, Chang YT, Chen CC, Lin KH, Tseng TH, Kargren M, Tai YL, Shen TL, Liu YL, Wang BJ, Chang CH, Chen WM, Juan HF, Huang SF, Chan YY, Liao YF, Hsu WM, Lee H. Activation of Aryl Hydrocarbon Receptor by Kynurenine Impairs Progression and Metastasis of Neuroblastoma. Cancer Res 2019; 79:5550-5562. [PMID: 31431462 DOI: 10.1158/0008-5472.can-18-3272] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 04/08/2019] [Accepted: 08/14/2019] [Indexed: 11/16/2022]
Abstract
Neuroblastoma is the most common malignant disease of infancy, and amplification of the MYCN oncogene is closely associated with poor prognosis. Recently, expression of MYCN was shown to be inversely correlated with aryl hydrocarbon receptor (AHR) expression in neuroblastoma, and overexpression of AHR downregulated MYCN expression, promoting cell differentiation. Therefore, we further investigated the potential of AHR to serve as a prognostic indicator or a therapeutic target in neuroblastoma. First, the clinical significance of AHR in neuroblastoma was examined. Positive AHR immunostaining strongly correlated with differentiated histology of neuroblastoma and predicted better survival for patients. The mouse xenograft model showed that overexpression of AHR significantly suppressed neuroblastoma tumor growth. In addition, activation of AHR by the endogenous ligand kynurenine inhibited cell proliferation and promoted cell differentiation in vitro and in vivo. kynurenine treatment also upregulated the expression of KISS1, a tumor metastasis suppressor, and attenuated metastasis in the xenograft model. Finally, analysis of KISS1 levels in neuroblastoma patient tumors using the R2: Genomics Analysis and Visualization Platform revealed that KISS1 expression positively correlated with AHR, and high KISS1 expression predicted better survival for patients. In conclusion, our results indicate that AHR is a novel prognostic biomarker for neuroblastoma, and that overexpression or activation of AHR offers a new therapeutic possibility for patients with neuroblastoma. SIGNIFICANCE: These findings show that AHR may function as a tumor suppressor in childhood neuroblastoma, potentially influencing the aetiologic and therapeutic targeting of the disease.
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Affiliation(s)
- Pei-Yi Wu
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - I-Shing Yu
- Laboratory Animal Center, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yueh-Chien Lin
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Yu-Tzu Chang
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Chien-Chin Chen
- Department of Pathology, Chia-Yi Christian Hospital, Chiayi, Taiwan.,Department of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Kuan-Hung Lin
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Tzu-Hsuan Tseng
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Mati Kargren
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Yu-Ling Tai
- Department of Plant Pathology and Microbiology & Center for Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Tang-Long Shen
- Department of Plant Pathology and Microbiology & Center for Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Yen-Lin Liu
- Department of Pediatrics, Taipei Medical University Hospital, Taipei, Taiwan
| | - Bo-Jeng Wang
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Chi-Hao Chang
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Wei-Min Chen
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Hsueh-Fen Juan
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Shiu-Feng Huang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County, Taiwan
| | - Ya-Yun Chan
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Yung-Feng Liao
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.,Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Wen-Ming Hsu
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
| | - Hsinyu Lee
- Department of Life Science, National Taiwan University, Taipei, Taiwan.
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28
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Deuster E, Mayr D, Hester A, Kolben T, Zeder-Göß C, Burges A, Mahner S, Jeschke U, Trillsch F, Czogalla B. Correlation of the Aryl Hydrocarbon Receptor with FSHR in Ovarian Cancer Patients. Int J Mol Sci 2019; 20:ijms20122862. [PMID: 31212758 PMCID: PMC6628023 DOI: 10.3390/ijms20122862] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 06/04/2019] [Accepted: 06/06/2019] [Indexed: 11/16/2022] Open
Abstract
Expression of the aryl hydrocarbon receptor (AhR) has been described in various tumor entities from different organs. However, its role in ovarian cancer has not been thoroughly investigated. We aimed to elucidate the prognostic impact of AhR, its correlation with the follicle-stimulating hormone receptor (FSHR), and their functional role in ovarian cancer. By immunohistochemistry, AhR staining was analyzed in a subset of 156 samples of ovarian cancer patients. AhR staining was assessed in the nucleus and the cytoplasm using the semi-quantitative immunoreactive score (IRS), and the scores were grouped into high- and low-level expression. AhR expression was detected in all histological subtypes, with clear cell ovarian cancer displaying the highest staining intensity. Low cytoplasmic expression of AhR was associated with longer overall survival (median 183.46 vs. 85.07 months; p = 0.021). We found a positive correlation between AhR and FSHR (p = 0.005). Ovarian cancer patients with high cytoplasmic AhR and concurrent FSHR expression had the worst outcome (median 69.72 vs. 43.32 months; p = 0.043). Consequently, low cytoplasmic AhR expression seems to be associated with improved survival in ovarian cancer patients. Our data suggest that AhR and FSHR levels correlate with each other, and their concurrent expression was observed in ovarian cancer patients with the worst outcome. Further investigation of the interaction of both receptors and their functional role might better predict the impact of endocrine therapy in ovarian cancer.
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Affiliation(s)
- Eileen Deuster
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany.
| | - Doris Mayr
- Institute of Pathology, Faculty of Medicine, LMU Munich, 81377 Munich, Germany.
| | - Anna Hester
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany.
| | - Thomas Kolben
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany.
| | - Christine Zeder-Göß
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany.
| | - Alexander Burges
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany.
| | - Sven Mahner
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany.
| | - Udo Jeschke
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany.
| | - Fabian Trillsch
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany.
| | - Bastian Czogalla
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany.
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29
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Yang Q, Salim L, Yan C, Gong Z. Rapid Analysis of Effects of Environmental Toxicants on Tumorigenesis and Inflammation Using a Transgenic Zebrafish Model for Liver Cancer. MARINE BIOTECHNOLOGY (NEW YORK, N.Y.) 2019; 21:396-405. [PMID: 30852708 DOI: 10.1007/s10126-019-09889-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 02/21/2019] [Indexed: 06/09/2023]
Abstract
Liver cancer remains to be a major health concern in the world today. Several major risk factors such as hepatitis viral infection and non-alcoholic steatohepatitis have been well established for causing liver cancer, but the contribution of environmental pollutants to liver inflammation and carcinogenesis remains poorly studied. Here, we aimed at the development of a rapid assay to test selected environmental toxicants for their potential roles in induction of inflammation and stimulation of liver tumorigenesis. By using an established kras oncogene transgenic zebrafish model for liver cancer, we tested a total of eight selected chemicals. First, using LPS (lipopolysaccharides) as a positive control, we confirmed its effects on induction of inflammation and stimulation of liver tumorigenesis as indicated by increases of neutrophils and the size of oncogenic livers respectively. Next, we tested two heavy metals (arsenic and chromium) and five organic toxicants (bisphenol A, lindane, N-nitrosodiethylamine, and 3,3',4,4',5-pentachlorobiphenyl [PCB126], and 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]). We observed a good correlation on induction of inflammation and their ability for stimulation of liver tumorigenesis. Most toxicants, namely chromium, bisphenol A, lindane, N-nitrosodiethylamine, and PCB126, resulted in increased inflammation and liver tumorigenesis, while arsenic and TCDD had opposite effects. Thus, our study established a screening system to rapidly assess the effects of candidate chemicals on liver tumorigenesis and inflammation.
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Affiliation(s)
- Qiqi Yang
- Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, Singapore
| | - Lyana Salim
- Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, Singapore
| | - Chuan Yan
- Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, Singapore
| | - Zhiyuan Gong
- Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, Singapore.
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30
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Bian Y, Li Y, Shrestha G, Wen X, Cai B, Wang K, Wan X. ITE, an endogenous aryl hydrocarbon receptor ligand, suppresses endometrial cancer cell proliferation and migration. Toxicology 2019; 421:1-8. [PMID: 30953668 DOI: 10.1016/j.tox.2019.03.017] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Revised: 02/16/2019] [Accepted: 03/29/2019] [Indexed: 01/16/2023]
Abstract
BACKGROUND Identification of new molecular targets for the treatment of endometrial cancer (EC) is an important clinical goal, especially for the patients which were resistant to conventional therapies. The aryl hydrocarbon receptor (AhR) is a ligand- activated transcription factor known primarily as the mediator of dioxin toxicity. However, the AhR can also inhibit cellular proliferation in a ligand-dependent manner and act as a tumor suppressor in mice, thus may be a potential anticancer target. In this study, we investigated if the endogenous AhR ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) regulated proliferation and migration of EC cells via AhR. METHODS We used quantitative real-time PCR and western blot to assess the expression of AhR in EC tissues and paired adjacent normal tissues. In addition, we conducted transwell assay to test whether the treatment of ITE altered the locomotive potential and proliferation of EC cells. Next, we conducted mouse xenograft models to further explore the in vivo effect of ITE. RESULTS We found that the AhR protein and RNA levels were increased mildly in EC tissues relative to the para-tumor normal endometrial tissues. Besides, ITE suppressed EC cells proliferation and migration in vitro, and also suppressed EC cells xenograft growth in mice. CONCLUSIONS Our results strongly supported the possibility of using the ITE as a small molecular compound for the treatment of EC.
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Affiliation(s)
- Yiding Bian
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Yiran Li
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Garima Shrestha
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Xiaoli Wen
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Bailian Cai
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Kai Wang
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, PR China.
| | - Xiaoping Wan
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, PR China.
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Yamaguchi M, Hankinson O. 2,3,7,8‑tetrachlorodibenzo‑p‑dioxin suppresses the growth of human colorectal cancer cells in vitro: Implication of the aryl hydrocarbon receptor signaling. Int J Oncol 2019; 54:1422-1432. [PMID: 30720065 PMCID: PMC6411353 DOI: 10.3892/ijo.2019.4703] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 12/18/2018] [Indexed: 12/22/2022] Open
Abstract
Human colorectal cancer is the third most common cancer disease with a 5‑year survival rate of 55% in USA in 2016. The investigation to identify novel biomarker factors with molecular classification may provide notable clinical information to prolong the survival of patients with colorectal cancer. The aryl hydrocarbon receptor (AHR) binds the AHR nuclear translocator in the cytoplasm of various types of cells, including liver cells, and then binds to the xenobiotic responsive element on various genes. AHR was initially discovered via its ligand, the polychlorinated hydrocarbon, 2,3,7,8‑tetrachlorodibenzo‑p‑dioxin (TCDD). The present study was undertaken to determine whether TCDD, an agonist of AHR signaling, impacts the growth of RKO human colorectal cancer cells in vitro. Treatment with TCDD (0.1‑100 nM) revealed suppressive effects on colony formation and proliferation of RKO cells, and stimulated death of these cells with subconfluence. These effects of TCDD were abolished by pretreatment with CH223191, an inhibitor of AHR signaling. Western blot analysis demonstrated that TCDD treatment decreased AHR levels and elevated cytochrome P450 family 1 subfamily A member 1 (CYP1A1) levels, indicating a stimulation of AHR signaling. TCDD treatment caused an increase in nuclear factor‑κB p65 and β‑catenin levels, although it did not have an effect on Ras levels. Notably, TCDD treatment increased the levels of p53, retinoblastoma, p21 and regucalcin, which are depressors of carcinogenesis. Additionally, action of TCDD on cell proliferation and death were not revealed in regucalcin‑overexpressing RKO cells, and regucalcin overexpression depressed AHR signaling associated with CYP1A1 expression. Thus, AHR signaling suppresses the growth of colorectal cancer cells, indicating a role as a significant targeting molecule for colorectal cancer.
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Affiliation(s)
- Masayoshi Yamaguchi
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), 700 Tiverton Avenue, Los Angeles, CA 90095‑1732, USA
| | - Oliver Hankinson
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), 700 Tiverton Avenue, Los Angeles, CA 90095‑1732, USA
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Scoville SD, Nalin AP, Chen L, Chen L, Zhang MH, McConnell K, Beceiro Casas S, Ernst G, Traboulsi AAR, Hashi N, Williams M, Zhang X, Hughes T, Mishra A, Benson DM, Saultz JN, Yu J, Freud AG, Caligiuri MA, Mundy-Bosse BL. Human AML activates the aryl hydrocarbon receptor pathway to impair NK cell development and function. Blood 2018; 132:1792-1804. [PMID: 30158248 PMCID: PMC6202909 DOI: 10.1182/blood-2018-03-838474] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 08/22/2018] [Indexed: 12/19/2022] Open
Abstract
Acute myeloid leukemia (AML) can evade the mouse and human innate immune system by suppressing natural killer (NK) cell development and NK cell function. This is driven in part by the overexpression of microRNA (miR)-29b in the NK cells of AML patients, but how this occurs is unknown. In the current study, we demonstrate that the transcription factor aryl hydrocarbon receptor (AHR) directly regulates miR-29b expression. We show that human AML blasts activate the AHR pathway and induce miR-29b expression in NK cells, thereby impairing NK cell maturation and NK cell function, which can be reversed by treating NK cells with an AHR antagonist. Finally, we show that inhibition of constitutive AHR activation in AML blasts lowers their threshold for apoptosis and decreases their resistance to NK cell cytotoxicity. Together, these results identify the AHR pathway as a molecular mechanism by which AML impairs NK cell development and function. The results lay the groundwork in establishing AHR antagonists as potential therapeutic agents for clinical development in the treatment of AML.
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MESH Headings
- Animals
- Gene Expression Regulation, Leukemic/genetics
- Humans
- Killer Cells, Natural/cytology
- Killer Cells, Natural/immunology
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/metabolism
- Mice
- MicroRNAs/biosynthesis
- Receptors, Aryl Hydrocarbon/metabolism
- Signal Transduction/physiology
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Affiliation(s)
| | - Ansel P Nalin
- Medical Scientist Training Program
- Comprehensive Cancer Center
| | - Luxi Chen
- Medical Scientist Training Program
- Comprehensive Cancer Center
| | | | | | | | | | | | | | | | | | | | - Tiffany Hughes
- Comprehensive Cancer Center
- Division of Hematology, Department of Internal Medicine
| | - Anjali Mishra
- Comprehensive Cancer Center
- Division of Dermatology, Department of Internal Medicine, and
| | - Don M Benson
- Comprehensive Cancer Center
- Division of Hematology, Department of Internal Medicine
| | - Jennifer N Saultz
- Comprehensive Cancer Center
- Division of Hematology, Department of Internal Medicine
| | - Jianhua Yu
- Comprehensive Cancer Center
- Division of Hematology, Department of Internal Medicine
| | - Aharon G Freud
- Comprehensive Cancer Center
- Department of Pathology, The Ohio State University, Columbus, OH; and
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33
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Liu WC, Tomino Y, Lu KC. Impacts of Indoxyl Sulfate and p-Cresol Sulfate on Chronic Kidney Disease and Mitigating Effects of AST-120. Toxins (Basel) 2018; 10:toxins10090367. [PMID: 30208594 PMCID: PMC6162782 DOI: 10.3390/toxins10090367] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 09/07/2018] [Accepted: 09/08/2018] [Indexed: 02/07/2023] Open
Abstract
Uremic toxins, such as indoxyl sulfate (IS) and p-cresol, or p-cresyl sulfate (PCS), are markedly accumulated in the organs of chronic kidney disease (CKD) patients. These toxins can induce inflammatory reactions and enhance oxidative stress, prompting glomerular sclerosis and interstitial fibrosis, to aggravate the decline of renal function. Consequently, uremic toxins play an important role in the worsening of renal and cardiovascular functions. Furthermore, they destroy the quantity and quality of bone. Oral sorbent AST-120 reduces serum levels of uremic toxins in CKD patients by adsorbing the precursors of IS and PCS generated by amino acid metabolism in the intestine. Accordingly, AST-120 decreases the serum IS levels and reduces the production of reactive oxygen species by endothelial cells, to impede the subsequent oxidative stress. This slows the progression of cardiovascular and renal diseases and improves bone metabolism in CKD patients. Although large-scale studies showed no obvious benefits from adding AST-120 to the standard therapy for CKD patients, subsequent sporadic studies may support its use. This article summarizes the mechanisms of the uremic toxins, IS, and PCS, and discusses the multiple effects of AST-120 in CKD patients.
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Affiliation(s)
- Wen-Chih Liu
- Division of Nephrology, Department of Internal Medicine, Tungs' Taichung Metro Harbor Hospital, Taichung City 435, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 106, Taiwan.
| | - Yasuhiko Tomino
- Asian Pacific Renal Research Promotion Office, Medical Corporation SHOWAKAI, Tokyo 160-0023, Japan.
| | - Kuo-Cheng Lu
- Division of Nephrology, Department of Medicine, Fu-Jen Catholic University Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei City 243, Taiwan.
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34
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Yamaguchi M, Hankinson O. 2,3,7,8‑Tetrachlorodibenzo‑p‑dioxin suppresses the growth of human liver cancer HepG2 cells in vitro: Involvement of cell signaling factors. Int J Oncol 2018; 53:1657-1666. [PMID: 30066859 PMCID: PMC6086623 DOI: 10.3892/ijo.2018.4507] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 06/27/2018] [Indexed: 12/29/2022] Open
Abstract
The aryl hydrocarbon receptor (AHR) is transcriptionally active in the form of a heterodimer with the AHR nuclear translocator, which then binds to the xenobiotic responsive element. AHR was originally discovered via its ligand, the polychlorinated hydrocarbon, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In this study, we investigated whether TCDD regulates the growth of human liver cancer HepG2 cells in vitro. TCDD (0.1–100 nM) was found to exert suppressive effects on the colony formation and proliferation of HepG2 cells, and stimulatory effects on the death of HepG2 cells when the cells reached subconfluence. The effects of TCDD on the HepG2 cells were abolished by culture with CH223191, an inhibitor of AHR signaling. The effects of TCDD were dependent on the concentration of serum, which contains various signaling factors. The effects of TCDD were not potentiated by culture with tumor necrosis factor-α, which activates the signaling of nuclear factor-κB (NF-κB). The results of western blot analysis revealed that TCDD increased the protein levels of p53, Rb, p21, and regucalcin, which are suppressors of the growth of tumor cells. Moreover, TCDD enhanced the NF-κB p65, β-catenin, signal transducer and activator of transcription 3 (STAT3), Ras and Akt levels. Thus, the findings of this study indicate that TCDD may suppress liver cancer cell growth through various signaling pathways, mediated by AHR and its-related co-factors. Of note, the effects of TCDD were found to be potentiated by gemcitabine, which induces nuclear DNA damage in cancer cells, suggesting that their combined use may have potential as a suppressor of tumor cell growth.
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Affiliation(s)
- Masayoshi Yamaguchi
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095‑1723, USA
| | - Oliver Hankinson
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095‑1723, USA
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35
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Larigot L, Juricek L, Dairou J, Coumoul X. AhR signaling pathways and regulatory functions. BIOCHIMIE OPEN 2018; 7:1-9. [PMID: 30003042 PMCID: PMC6039966 DOI: 10.1016/j.biopen.2018.05.001] [Citation(s) in RCA: 378] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Accepted: 05/28/2018] [Indexed: 12/12/2022]
Abstract
Animals and humans are exposed each day to a multitude of chemicals in the air, water and food. They have developed a battery of enzymes and transporters that facilitate the biotransformation and elimination of these compounds. Moreover, a majority of these enzymes and transporters are inducible due to the activation of xenobiotic receptors which act as transcription factors for the regulation of their target genes (such as xenobiotic metabolizing enzymes, see below §4 for the AhR). These receptors include several members of the nuclear/steroid receptor family (CAR for Constitutive Androstane Receptor, PXR for Pregnane X Receptor) but also the Aryl hydrocarbon Receptor or AhR, a member of the bHLH-PAS family (basic Helix-Loop-Helix - Period/ARNT/Single minded). In addition to the regulation of xenobiotic metabolism, numerous alternative functions have been characterized for the AhR since its discovery. These alternative functions will be described in this review along with its endogenous functions as revealed by experiments performed on knock-out animals.
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Affiliation(s)
- Lucie Larigot
- INSERM UMR-S 1124, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des Saints-Pères, 75006 Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Saints-Pères, 75006 Paris, France
| | - Ludmila Juricek
- INSERM UMR-S 1124, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des Saints-Pères, 75006 Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Saints-Pères, 75006 Paris, France
| | - Julien Dairou
- CNRS 8601, 45 rue des Saints-Pères, 75006 Paris, France
| | - Xavier Coumoul
- INSERM UMR-S 1124, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des Saints-Pères, 75006 Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Saints-Pères, 75006 Paris, France
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36
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Towards Resolving the Pro- and Anti-Tumor Effects of the Aryl Hydrocarbon Receptor. Int J Mol Sci 2018; 19:ijms19051388. [PMID: 29735912 PMCID: PMC5983651 DOI: 10.3390/ijms19051388] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 04/27/2018] [Accepted: 04/30/2018] [Indexed: 12/11/2022] Open
Abstract
We have postulated that the aryl hydrocarbon receptor (AHR) drives the later, more lethal stages of some cancers when chronically activated by endogenous ligands. However, other studies have suggested that, under some circumstances, the AHR can oppose tumor aggression. Resolving this apparent contradiction is critical to the design of AHR-targeted cancer therapeutics. Molecular (siRNA, shRNA, AHR repressor, CRISPR-Cas9) and pharmacological (AHR inhibitors) approaches were used to confirm the hypothesis that AHR inhibition reduces human cancer cell invasion (irregular colony growth in 3D Matrigel cultures and Boyden chambers), migration (scratch wound assay) and metastasis (human cancer cell xenografts in zebrafish). Furthermore, these assays were used for a head-to-head comparison between AHR antagonists and agonists. AHR inhibition or knockdown/knockout consistently reduced human ER−/PR−/Her2− and inflammatory breast cancer cell invasion, migration, and metastasis. This was associated with a decrease in invasion-associated genes (e.g., Fibronectin, VCAM1, Thrombospondin, MMP1) and an increase in CDH1/E-cadherin, previously associated with decreased tumor aggression. Paradoxically, AHR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin and/or 3,3′-diindolylmethane) similarly inhibited irregular colony formation in Matrigel and blocked metastasis in vivo but accelerated migration. These data demonstrate the complexity of modulating AHR activity in cancer while suggesting that AHR inhibitors, and, under some circumstances, AHR agonists, may be useful as cancer therapeutics.
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37
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Mescher M, Haarmann-Stemmann T. Modulation of CYP1A1 metabolism: From adverse health effects to chemoprevention and therapeutic options. Pharmacol Ther 2018; 187:71-87. [PMID: 29458109 DOI: 10.1016/j.pharmthera.2018.02.012] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The human cytochrome P450 (CYP) 1A1 gene encodes a monooxygenase that metabolizes multiple exogenous and endogenous substrates. CYP1A1 has become infamous for its oxidative metabolism of benzo[a]pyrene and related polycyclic aromatic hydrocarbons, converting these chemicals into very potent human carcinogens. CYP1A1 expression is mainly controlled by the aryl hydrocarbon receptor (AHR), a transcription factor whose activation is induced by binding of persistent organic pollutants, including polycyclic aromatic hydrocarbons and dioxins. Accordingly, induction of CYP1A1 expression and activity serves as a biomarker of AHR activation and associated xenobiotic metabolism as well as toxicity in diverse animal species and humans. Determination of CYP1A1 activity is integrated into modern toxicological concepts and testing guidelines, emphasizing the tremendous importance of this enzyme for risk assessment and regulation of chemicals. Further, CYP1A1 serves as a molecular target for chemoprevention of chemical carcinogenesis, although present literature is controversial on whether its inhibition or induction exerts beneficial effects. Regarding therapeutic applications, first anti-cancer prodrugs are available, which require a metabolic activation by CYP1A1, and thus enable a specific elimination of CYP1A1-positive tumors. However, the application range of these drugs may be limited due to the frequently observed downregulation of CYP1A1 in various human cancers, probably leading to a reduced metabolism of endogenous AHR ligands and a sustained activation of AHR and associated tumor-promoting responses. We here summarize the current knowledge on CYP1A1 as a key player in the metabolism of exogenous and endogenous substrates and as a promising target molecule for prevention and treatment of human malignancies.
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Affiliation(s)
- Melina Mescher
- IUF - Leibniz-Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany
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38
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Ye M, Zhang Y, Gao H, Xu Y, Jing P, Wu J, Zhang X, Xiong J, Dong C, Yao L, Zhang J, Zhang J. Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non-Small Cell Lung Cancer by Activating Src-mediated Bypass Signaling. Clin Cancer Res 2017; 24:1227-1239. [PMID: 29229632 DOI: 10.1158/1078-0432.ccr-17-0396] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 07/08/2017] [Accepted: 12/05/2017] [Indexed: 11/16/2022]
Abstract
Purpose: The aryl hydrocarbon receptor (AhR) has been generally recognized as a ligand-activated transcriptional factor that responds to xenobiotic chemicals. Recent studies have suggested that the expression of AhR varies widely across different cancer types and cancer cell lines, but its significance in cancer treatment has yet to be clarified.Experimental Design: AhR expression in non-small cell lung cancer (NSCLC) was determined by Western blotting and IHC staining. In vitro and in vivo functional experiments were performed to determine the effect of AhR on sensitivity to targeted therapeutics. A panel of biochemical assays was used to elucidate the underlying mechanisms.Results: A high AhR protein level indicated an unfavorable prognosis for lung adenocarcinoma. Inhibition of AhR signaling sensitized EGFR tyrosine kinase inhibitors (TKIs) in NSCLC cells that express high level of endogenous AhR protein. Notably, activation of AhR by pharmacologic and molecular approaches rendered EGFR-mutant cells resistant to TKIs by restoring PI3K/Akt and MEK/Erk signaling through activation of Src. In addition, we found that AhR acts as a protein adaptor to mediate Jak2-Src interaction, which does not require the canonical transcriptional activity of AhR.Conclusions: Our results reveal a transcription-independent function of AhR and indicate that AhR may act as a protein adaptor that recruits kinases bypassing EGFR and drives resistance to TKIs. Accordingly, targeting Src would be a strategy to overcome resistance to EGFR TKIs in AhR-activated NSCLC. Clin Cancer Res; 24(5); 1227-39. ©2017 AACR.
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Affiliation(s)
- Mingxiang Ye
- Department of Pulmonary Medicine, Xijing Hospital, Xi'an, China.,State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Yong Zhang
- Department of Pulmonary Medicine, Xijing Hospital, Xi'an, China
| | - Hongjun Gao
- Department of Pulmonary Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Yan Xu
- Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Pengyu Jing
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Jianxiong Wu
- Department of Pulmonary Medicine, Xijing Hospital, Xi'an, China
| | - Xinxin Zhang
- Department of Pulmonary Medicine, Xijing Hospital, Xi'an, China
| | - Jie Xiong
- Department of Pulmonary Medicine, Xijing Hospital, Xi'an, China
| | - Chenfang Dong
- Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China
| | - Libo Yao
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Jian Zhang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
| | - Jian Zhang
- Department of Pulmonary Medicine, Xijing Hospital, Xi'an, China.
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Zhang H, Li L, Li M, Huang X, Xie W, Xiang W, Yao P. Combination of betulinic acid and chidamide inhibits acute myeloid leukemia by suppression of the HIF1α pathway and generation of reactive oxygen species. Oncotarget 2017; 8:94743-94758. [PMID: 29212263 PMCID: PMC5706909 DOI: 10.18632/oncotarget.21889] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 09/24/2017] [Indexed: 12/04/2022] Open
Abstract
Acute myeloid leukemia (AML) is a heterogeneous disorder of the hematopoietic system with no common genetic “Achilles heel” that can be targeted. Most patients respond well to standard therapy, while a majority relapse, and development of an effective therapy for AML patients is still urgently needed. In this study, we demonstrated that betulinic acid (BA) significantly increased Aryl hydrocarbon receptor (AHR) expression through demethylation on the AHR promoter in AML cells, and the increased AHR expression interacts with and sequesters ARNT, subsequently suppressing hypoxia-inducible factor-1α (HIF1α) pathway. We also found that histone deacetylase inhibitor chidamide (CDM) treatment significantly increased p300 over-acetylation in AML cells with dissociation of p300 with HIF1α, and subsequently suppressed the HIF1α pathway. Further investigation showed that BA/CDM combination additively increased generation of reactive oxygen species (ROS) with DNA damage, apoptosis and mitochondrial dysfunction. Also, BA/CDM combination additively suppressed the HIF1α pathway with decreased VEGF expression. in vivo mice study showed that BA/CDM combination significantly suppressed AML tumor growth, and overexpression of SOD2 and a constitutive HIF1α (HIF1C) completely diminished this effect. We conclude that a BA/CDM combination inhibits AML tumors through ROS over-generation and HIF1α pathway suppression. This is the first time we have shown the potential effect and possible mechanism of BA and CDM on the inhibition of AML tumor growth.
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Affiliation(s)
- Hongyu Zhang
- Department of Hematology, Peking University Shenzhen Hospital, Shenzhen 518036, P.R. China
| | - Ling Li
- Department of Pediatrics, Maternal and Child Health Care Hospital of Hainan Province, Haikou 570206, P.R. China
| | - Min Li
- Institute of Burns, Tongren Hospital of Wuhan University, Wuhan 430060, P.R. China
| | - Xiaodong Huang
- Institute of Burns, Tongren Hospital of Wuhan University, Wuhan 430060, P.R. China
| | - Weiguo Xie
- Institute of Burns, Tongren Hospital of Wuhan University, Wuhan 430060, P.R. China
| | - Wei Xiang
- Department of Pediatrics, Maternal and Child Health Care Hospital of Hainan Province, Haikou 570206, P.R. China
| | - Paul Yao
- Department of Hematology, Peking University Shenzhen Hospital, Shenzhen 518036, P.R. China.,Department of Pediatrics, Maternal and Child Health Care Hospital of Hainan Province, Haikou 570206, P.R. China.,Institute of Burns, Tongren Hospital of Wuhan University, Wuhan 430060, P.R. China
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Abstract
Pituitary adenomas (PA) represent the largest group of intracranial neoplasms and yet the molecular mechanisms driving this disease remain largely unknown. The aim of this study was to use a high-throughput screening method to identify molecular pathways that may be playing a significant and consistent role in PA. RNA profiling using microarrays on eight local PAs identified the aryl hydrocarbon receptor (AHR) signalling pathway as a key canonical pathway downregulated in all PA types. This was confirmed by real-time PCR in 31 tumours. The AHR has been shown to regulate cell cycle progression in various cell types; however, its role in pituitary tissue has never been investigated. In order to validate the role of AHR in PA behaviour, further functional studies were undertaken. Over-expression of AHR in GH3 cells revealed a tumour suppressor potential independent of exogenous ligand activation by benzo α-pyrene (BαP). Cell cycle analysis and quantitative PCR of cell cycle regulator genes revealed that both unstimulated and BαP-stimulated AHR reduced E2F-driven transcription and altered expression of cell cycle regulator genes, thus increasing the percentage of cells in G0/G1 phase and slowing the proliferation rate of GH3 cells. Co-immunoprecipitation confirmed the interaction between AHR and retinoblastoma (Rb1) protein supporting this as a functional mechanism for the observed reduction. Endogenous Ahr reduction using silencing RNA confirmed the tumour suppressive function of the Ahr. These data support a mechanistic pathway for the putative tumour suppressive role of AHR specifically in PA, possibly through its role as a cell cycle co-regulator, even in the absence of exogenous ligands.
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Affiliation(s)
- R Formosa
- Department of MedicineFaculty of Medicine and Surgery, University of Malta, Msida, Malta
| | - J Borg
- Department of Applied Biomedical ScienceFaculty of Health Sciences, University of Malta, Msida, Malta
| | - J Vassallo
- Department of MedicineFaculty of Medicine and Surgery, University of Malta, Msida, Malta
- Department of MedicineNeuroendocrine Clinic, Mater Dei Hospital, Msida, Malta
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A Molecular Mechanism To Switch the Aryl Hydrocarbon Receptor from a Transcription Factor to an E3 Ubiquitin Ligase. Mol Cell Biol 2017; 37:MCB.00630-16. [PMID: 28416634 DOI: 10.1128/mcb.00630-16] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 04/10/2017] [Indexed: 01/01/2023] Open
Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is known as a mediator of toxic responses. Recently, it was shown that the AhR has dual functions. Besides being a transcription factor, it also possesses an intrinsic E3 ubiquitin ligase function that targets, e.g., the steroid receptors for proteasomal degradation. The aim of this study was to identify the molecular switch that determines whether the AhR acts as a transcription factor or an E3 ubiquitin ligase. To do this, we used the breast cancer cell line MCF7, which expresses a functional estrogen receptor alpha (ERα) signaling pathway. Our data suggest that aryl hydrocarbon receptor nuclear translocator (ARNT) plays an important role in the modulation of the dual functions of the AhR. ARNT knockdown dramatically impaired the transcriptional activation properties of the ligand-activated AhR but did not affect its E3 ubiquitin ligase function. The availability of ARNT itself is modulated by another basic helix-loop-helix (bHLH)-Per-ARNT-SIM (PAS) protein, the repressor of AhR function (AhRR). MCF7 cells overexpressing the AhRR showed lower ERα protein levels, reduced responsiveness to estradiol, and reduced growth rates. Importantly, when these cells were used to produce estrogen-dependent xenograft tumors in SCID mice, we also observed lower ERα protein levels and a reduced tumor mass, implying a tumor-suppressive-like function of the AhR in MCF7 xenograft tumors.
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Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target. Arch Toxicol 2017; 91:2497-2513. [PMID: 28508231 DOI: 10.1007/s00204-017-1981-2] [Citation(s) in RCA: 119] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 05/08/2017] [Indexed: 12/31/2022]
Abstract
The aryl hydrocarbon receptor (AhR) was initially identified as the receptor that binds and mediates the toxic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and structurally related halogenated aromatics. Other toxic compounds including some polynuclear aromatic hydrocarbons act through the AhR; however, during the last 25 years, it has become apparent that the AhR plays an essential role in maintaining cellular homeostasis. Moreover, the scope of ligands that bind the AhR includes endogenous compounds such as multiple tryptophan metabolites, other endogenous biochemicals, pharmaceuticals and health-promoting phytochemicals including flavonoids, indole-3-carbinol and its metabolites. It has also been shown that like other receptors, the AhR is a drug target for multiple diseases including cancer, where both AhR agonists and antagonists effectively block many of the critical hallmarks of cancer in multiple tumor types. This review describes the anti-cancer activities of AhR ligands and demonstrates that it is time to separate the AhR from TCDD and exploit the potential of the AhR as a novel target for cancer chemotherapy.
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Megna BW, Carney PR, Depke MG, Nukaya M, McNally J, Larsen L, Rosengren RJ, Kennedy GD. The aryl hydrocarbon receptor as an antitumor target of synthetic curcuminoids in colorectal cancer. J Surg Res 2017; 213:16-24. [PMID: 28601309 DOI: 10.1016/j.jss.2017.02.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Revised: 01/08/2017] [Accepted: 02/14/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Curcumin has proven to be a potent antitumor agent in both preclinical and clinical models of colorectal cancer (CRC). It has also been identified as a ligand of the transcription factor known as the aryl hydrocarbon receptor (AHR). Our laboratory has identified the AHR as a mechanism which contributes to both tumorigenesis in a mouse model of inflammatory CRC as well an apoptotic target in vitro. Curcumin's role as an AHR ligand may modulate its effects to induce colon cancer cell death, and this role may be enhanced via structural modification of the curcumin backbone. We sought to determine if the two piperidone analogs of curcumin, RL66 and RL118, exhibit more robust antitumor actions than their parent compound in the context of colorectal cancer in vitro. Moreover, to ascertain the ability of curcumin, RL66 and RL118 to activate the AHR and evaluate if this activation has any effect on CRC cell death. MATERIALS AND METHODS DLD1, HCT116, LS513, and RKO colon cell lines were propagated in vitro. Natural curcumin was obtained commercially, whereas RL66 and RL118 were synthesized and characterized de novo. Multiwell fluorescent/luminescent signal detection was used to simultaneously ascertain cell viability, cell cytonecrosis, and relative amounts of apoptotic activity. AHR activity was measured with a dual luciferase reporter gene system. Stable expression of small interfering RNA interference was established in the HCT116 cell lines to create AHR "knock down" cell lines. RESULTS Both RL66 and RL118 proved to be more potent antitumor agents than their parent compound curcumin in all cell lines tested. The majority of this cell death was due to induction of apoptosis, which occurred earlier and to a greater degree following RL66 and RL118 treatment as opposed to curcumin. Also, RL66 and RL118 were found to be activators of AHR, and a portion of their ability to cause cell death was dependent on this induction. Curcumin was found unable to activate the AHR, and levels of AHR messenger RNA did not change their effects on cell death. CONCLUSIONS Piperidone analogs of curcumin exhibited enhanced antitumor effects in vitro as opposed to their parent compound. Even more, this enhanced cell death profile may be partially attributed to the ability of these compounds to activate the AHR. Further study of synthetic curcumin analogs as chemopreventives and chemoadjuncts in CRC is warranted. Also, more generally, the AHR may represent a potential putative target for novel anticancer agents for CRC.
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Affiliation(s)
- Bryant W Megna
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Patrick R Carney
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Mitchell G Depke
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Manabu Nukaya
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - James McNally
- Department of Chemistry, University of Otago, Dunedin, New Zealand
| | - Lesley Larsen
- Department of Chemistry, University of Otago, Dunedin, New Zealand
| | - Rhonda J Rosengren
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
| | - Gregory D Kennedy
- Department of Surgery, University of Alabama-Birmingham School of Medicine, Birmingham, Alabama.
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Wang Z, Monti S, Sherr DH. The diverse and important contributions of the AHR to cancer and cancer immunity. CURRENT OPINION IN TOXICOLOGY 2017. [DOI: 10.1016/j.cotox.2017.01.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Cuartero MI, de la Parra J, García-Culebras A, Ballesteros I, Lizasoain I, Moro MÁ. The Kynurenine Pathway in the Acute and Chronic Phases of Cerebral Ischemia. Curr Pharm Des 2016; 22:1060-73. [PMID: 25248805 DOI: 10.2174/1381612822666151214125950] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Accepted: 12/11/2015] [Indexed: 12/12/2022]
Abstract
Kynurenines are a wide range of catabolites which derive from tryptophan through the "Kynurenine Pathway" (KP). In addition to its peripheral role, increasing evidence shows a role of the KP in the central nervous system (CNS), mediating both physiological and pathological functions. Indeed, an imbalance in this route has been associated with several neurodegenerative disorders such as Alzheimer´s and Huntington´s diseases. Altered KP catabolism has also been described during both acute and chronic phases of stroke; however the contribution of the KP to the pathophysiology of acute ischemic damage and of post-stroke disorders during the chronic phase including depression and vascular dementia, and the exact mechanisms implicated in the regulation of the KP after stroke are not well established yet. A better understanding of the regulation and activity of the KP after stroke could provide new pharmacological tools in both acute and chronic phases of stroke. In this review, we will make an overview of CNS modulation by the KP. We will detail the KP contribution in the ischemic damage, how the unbalance of the KP might trigger an alteration of the cognitive function after stroke as well as potential targets for the development of new drugs.
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Affiliation(s)
- María Isabel Cuartero
- Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Avenida Complutense s/n, 28040 Madrid, Spain.
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Li CH, Liu CW, Tsai CH, Peng YJ, Yang YH, Liao PL, Lee CC, Cheng YW, Kang JJ. Cytoplasmic aryl hydrocarbon receptor regulates glycogen synthase kinase 3 beta, accelerates vimentin degradation, and suppresses epithelial-mesenchymal transition in non-small cell lung cancer cells. Arch Toxicol 2016; 91:2165-2178. [PMID: 27752740 PMCID: PMC5399057 DOI: 10.1007/s00204-016-1870-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 10/06/2016] [Indexed: 02/06/2023]
Abstract
Aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, has been studied extensively in carcinogenesis through the genomic pathway. In recent years, AHR has also been reported to exert positive or negative effects on epithelial–mesenchymal transition (EMT), the crucial step in tumor malignant progression. However, the detailed mechanism remains controversial. Analysis of AHR-expression levels in non-small cell lung cancer cell lines and lung cancer tissues revealed an inverse correlation between AHR protein levels and tumor cell invasion and metastasis. Overexpression of wild-type AHR in H1299 cells (AHR poorly expressed, potently invasive) not only accelerated mesenchymal vimentin degradation, but also prevented cell invasion in vitro and in vivo. In the absence of AHR agonists, the overexpressed AHR protein was predominantly localized in the cytoplasm, where it interacted with vimentin and functioned as an E3 ubiquitin ligase. A 6-h incubation with the proteasome inhibitor MG-132 fully rescued vimentin from AHR-mediated proteasomal degradation. In AHR-overexpressing H1299 cells, either vimentin degradation or invasive suppression could be reversed when glycogen synthase kinase 3 beta (GSK3β) was inactivated by CHIR-99021 treatment. In contrast, silencing of AHR in A549 cells (AHR highly expressed, weakly invasive) resulted in the downregulation of epithelial biomarkers (E-cadherin and claudin-1), augmentation of mesenchymal vimentin level, and GSK3β Ser-9 hyper-phosphorylation, which led to enhanced invasiveness. This work demonstrates that cytoplasmic, resting AHR protein may act as an EMT suppressor via a non-genomic pathway. Depletion of cytoplasmic AHR content represents a potential switch for EMT, thereby leading to the scattering of tumor cells.
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Affiliation(s)
- Ching-Hao Li
- Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chen-Wei Liu
- School of Pharmacy, Taipei Medicine University, 250 Wu-Hsing Street, Taipei, Taiwan
| | - Chi-Hao Tsai
- Institute of Toxicology, College of Medicine, National Taiwan University, 1 Jen-Ai Road, Section 1, Taipei 10, Taiwan
| | - Yi-Jen Peng
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yu-Hsuan Yang
- Institute of Toxicology, College of Medicine, National Taiwan University, 1 Jen-Ai Road, Section 1, Taipei 10, Taiwan
| | - Po-Lin Liao
- Institute of Toxicology, College of Medicine, National Taiwan University, 1 Jen-Ai Road, Section 1, Taipei 10, Taiwan
| | - Chen-Chen Lee
- Department of Microbiology and Immunology, School of Medicine, China Medicine University, Taichung, Taiwan
| | - Yu-Wen Cheng
- School of Pharmacy, Taipei Medicine University, 250 Wu-Hsing Street, Taipei, Taiwan.
| | - Jaw-Jou Kang
- Institute of Toxicology, College of Medicine, National Taiwan University, 1 Jen-Ai Road, Section 1, Taipei 10, Taiwan.
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Yang F, Yang H, Ramesh A, Goodwin JS, Okoro EU, Guo Z. Overexpression of Catalase Enhances Benzo(a)pyrene Detoxification in Endothelial Microsomes. PLoS One 2016; 11:e0162561. [PMID: 27607467 PMCID: PMC5015903 DOI: 10.1371/journal.pone.0162561] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 08/24/2016] [Indexed: 02/07/2023] Open
Abstract
We previously reported that overexpression of catalase upregulated xenobiotic- metabolizing enzyme (XME) expression and diminished benzo(a)pyrene (BaP) intermediate accumulation in mouse aortic endothelial cells (MAECs). Endoplasmic reticulum (ER) is the most active organelle involved in BaP metabolism. To examine the involvement of ER in catalase-induced BaP detoxification, we compared the level and distribution of XMEs, and the profile of BaP intermediates in the microsomes of wild-type and catalase transgenic endothelial cells. Our data showed that endothelial microsomes were enriched in cytochrome P450 (CYP) 1A1, CYP1B1 and epoxide hydrolase 1 (EH1), and contained considerable levels of NAD(P)H: quinone oxidoreductase-1 (NQO1) and glutathione S-transferase-pi (GSTP). Treatment of wild-type MAECs with 1μM BaP for 2 h increased the expression of microsomal CYP1A1, 1B1 and NQO1 by ~300, 64 and 116%, respectively. However, the same treatment did not significantly alter the expression of EH1 and GSTP. Overexpression of catalase did not significantly increase EH1, but upregulated BaP-induced expression of microsomal CYP1A1, 1B1, NQO1 and GSTP in the following order: 1A1>NQO1>GSTP>1B1. Overexpression of catalase did not alter the distribution of each of these enzymes in the microsomes. In contrast to our previous report showing lower level of BaP phenols versus BaP diols/diones in the whole-cell, this report demonstrated that the sum of microsomal BaP phenolic metabolites were ~60% greater than that of the BaP diols/diones after exposure of microsomes to BaP. Overexpression of catalase reduced the concentrations of microsomal BaP phenols and diols/diones by ~45 and 95%, respectively. This process enhanced the ratio of BaP phenol versus diol/dione metabolites in a potent manner. Taken together, upregulation of phase II XMEs and CYP1 proteins, but not EH1 in the ER might be the mechanism by which overexpression of catalase reduces the levels of all the BaP metabolites, and enhances the ratio of BaP phenolic metabolites versus diol/diones in endothelial microsomes.
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Affiliation(s)
- Fang Yang
- Department of Physiology, Meharry Medical College, Nashville, United States of America.,Wuhan University School of Basic Medical Science, Wuhan, P.R. China
| | - Hong Yang
- Department of Physiology, Meharry Medical College, Nashville, United States of America
| | - Aramandla Ramesh
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, United States of America
| | - J Shawn Goodwin
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, United States of America
| | - Emmanuel U Okoro
- Department of Physiology, Meharry Medical College, Nashville, United States of America
| | - ZhongMao Guo
- Department of Physiology, Meharry Medical College, Nashville, United States of America
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Wojdylo JV, Vogelbein W, Bain LJ, Rice CD. AHR-related activities in a creosote-adapted population of adult atlantic killifish, Fundulus heteroclitus, two decades post-EPA superfund status at the Atlantic Wood Site, Portsmouth, VA USA. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2016; 177:74-85. [PMID: 27262937 PMCID: PMC4967385 DOI: 10.1016/j.aquatox.2016.05.021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 05/17/2016] [Accepted: 05/21/2016] [Indexed: 05/04/2023]
Abstract
Atlantic killifish, Fundulus heteroclitus, are adapted to creosote-based PAHs at the US EPA Superfund site known as Atlantic Wood (AW) on the southern branch of the Elizabeth River, VA USA. Subsequent to the discovery of the AW population in the early 1990s, these fish were shown to be recalcitrant to CYP1A induction by PAHs under experimental conditions, and even to the time of this study, killifish embryos collected from the AW site are resistant to developmental deformities typically associated with exposure to PAHs in reference fish. Historically, however, 90 +% of the adult killifish at this site have proliferative hepatic lesions including cancer of varying severity. Several PAHs at this site are known to be ligands for the aryl hydrocarbon receptor (AHR). In this study, AHR-related activities in AW fish collected between 2011 and 2013 were re-examined nearly 2 decades after first discovery. This study shows that CYP1A mRNA expression is three-fold higher in intestines of AW killifish compared to a reference population. Using immunohistochemistry, CYP1A staining in intestines was uniformly positive compared to negative staining in reference fish. Livers of AW killifish were examined by IHC to show that CYP1A and AHR2 protein expression reflect lesions-specific patterns, probably representing differences in intrinsic cellular physiology of the spectrum of proliferative lesions comprising the hepatocarcinogenic process. We also found that COX2 mRNA expression levels were higher in AW fish livers compared to those in the reference population, suggesting a state of chronic inflammation. Overall, these findings suggest that adult AW fish are responsive to AHR signaling, and do express CYP1A and AHR2 proteins in intestines at a level above what was observed in the reference population.
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Affiliation(s)
- Josephine V Wojdylo
- Department of Biological Sciences, Environmental Toxicology Graduate Program, Clemson University, Clemson, SC 29634, USA
| | | | - Lisa J Bain
- Department of Biological Sciences, Environmental Toxicology Graduate Program, Clemson University, Clemson, SC 29634, USA
| | - Charles D Rice
- Department of Biological Sciences, Environmental Toxicology Graduate Program, Clemson University, Clemson, SC 29634, USA.
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Mutz CN, Schwentner R, Kauer MO, Katschnig AM, Kromp F, Aryee DNT, Erhardt S, Goiny M, Alonso J, Fuchs D, Kovar H. EWS-FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway. FEBS Lett 2016; 590:2063-75. [PMID: 27282934 PMCID: PMC4988508 DOI: 10.1002/1873-3468.12243] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 05/30/2016] [Accepted: 06/06/2016] [Indexed: 01/14/2023]
Abstract
Ewing sarcoma (ES) is an aggressive pediatric tumor driven by the fusion protein EWS-FLI1. We report that EWS-FLI1 suppresses TDO2-mediated tryptophan (TRP) breakdown in ES cells. Gene expression and metabolite analyses reveal an EWS-FLI1-dependent regulation of TRP metabolism. TRP consumption increased in the absence of EWS-FLI1, resulting in kynurenine and kynurenic acid accumulation, both aryl hydrocarbon receptor (AHR) ligands. Activated AHR binds to the promoter region of target genes. We demonstrate that EWS-FLI1 knockdown results in AHR nuclear translocation and activation. Our data suggest that EWS-FLI1 suppresses autocrine AHR signaling by inhibiting TDO2-catalyzed TRP breakdown.
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Affiliation(s)
- Cornelia N Mutz
- Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria
| | - Raphaela Schwentner
- Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria
| | - Maximilian O Kauer
- Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria
| | - Anna M Katschnig
- Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria
| | - Florian Kromp
- Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria
| | - Dave N T Aryee
- Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.,Department of Pediatrics, Medical University Vienna, Austria
| | - Sophie Erhardt
- Department of Physiology and Pharmacology, Karolinska Institutet Stockholm, Sweden
| | - Michel Goiny
- Department of Physiology and Pharmacology, Karolinska Institutet Stockholm, Sweden
| | - Javier Alonso
- Unidad de Tumores Sólidos Infantiles, Instituto de Investigación de Enfermedades Raras, ISCIII, Ctra, Madrid, Spain
| | - Dietmar Fuchs
- Division of Biological Chemistry, Biocenter Innsbruck Medical University, Center for Chemistry and Biomedicine, Austria
| | - Heinrich Kovar
- Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.,Department of Pediatrics, Medical University Vienna, Austria
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50
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Baginskaya NV, Kashina EV, Shamanina MY, Ilnitskaya SI, Kaledin VI, Mordvinov VA. Correlation of susceptibility to ortho-aminoazotoluene-induced hepatocarcinogenesis with Car and Ahr signaling pathway activation in mice. ACTA ACUST UNITED AC 2016. [DOI: 10.1134/s2079059716040043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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