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Pei T, Li W, Zhou Z, Zhang Q, Yu G, Yin S, Chen H, Tang J. The relationship between tryptophan metabolism and gut microbiota: Interaction mechanism and potential effects in infection treatment. Microbiol Res 2025; 298:128211. [PMID: 40393170 DOI: 10.1016/j.micres.2025.128211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 04/29/2025] [Accepted: 05/05/2025] [Indexed: 05/22/2025]
Abstract
Human health is influenced by the gut microbiota, particularly in aspects of host immune homeostasis and intestinal immune response. Tryptophan (Trp) not only acts as a nutrient enhancer but also plays a critical role in the balance between host immune tolerance and gut microbiota maintenance. Both endogenous and bacterial metabolites of Trp, exert significant effects on gut microbial composition, microbial metabolism, the host immunity and the host-microbiome interface. Trp metabolites regulate host immunity by activating aryl hydrocarbon receptor (AhR), thereby contributing to immune homeostasis. Among Trp metabolites, AhR ligands include endogenous metabolites (such as kynurenine), and bacterial metabolites (such as indole and its derivatives). Here, we present a comprehensive analysis of the relationships between Trp metabolism and 14 key microbiota, encompassing fungi (e.g., Candida albicans, Aspergillus), bacteria (e.g., Ruminococcus gnavus, Bacteroides, Prevotella copri, Clostridium difficile, Escherichia coli, lactobacilli, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Staphylococcus aureus, Helicobacter. Pylori), and viruses (e.g., SARS-CoV-2, influenza virus). This review clarifies how the gut microbiota regulates Trp metabolism and uncovers the underlying mechanisms of these interactions. And increased mechanistic insight into how the microbiota modulate the host immune system through Trp metabolism may allow for the identification of innovative therapies that are specifically designed to target Trp absorption, Trp metabolites, the gut microbiota, or interactions between Trp and gut microbiota to treat both intestinal and extra-intestinal inflammation as well as microbial infections.
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Affiliation(s)
- Tongchao Pei
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
| | - Wenweiran Li
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
| | - Ziyang Zhou
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
| | - Qinyu Zhang
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
| | - Guohong Yu
- Department of Emergency Medicine, Baoshan Second People's Hospital, Baoshan College of Traditional Chinese Medicine, Baoshan 678000, China
| | - Sokun Yin
- Department of Emergency Medicine, Luoping County People's Hospital, Qujing 655800, China
| | - Hui Chen
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
| | - Jianguo Tang
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
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Swain J, Preeti, Mohanty C, Bajoria AA, Patnaik S, Ward Gahlawat A, Nikhil K, Mohapatra SR. Deciphering the metabolic landscape of colorectal cancer through the lens of AhR-mediated intestinal inflammation. Discov Oncol 2025; 16:275. [PMID: 40053174 DOI: 10.1007/s12672-025-01949-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/06/2025] [Indexed: 03/10/2025] Open
Abstract
Colorectal cancer (CRC) ranks as the third most common cancer worldwide, with its incidence steadily increasing due to an aging demographic and various lifestyle-related risk factors, including poor nutrition, tobacco use, sedentary behaviour and obesity. These factors promote the risk of colorectal cancer by inducing chronic colonic inflammation, a principal catalyst of carcinogenesis. This review delves into evidence that suggests that metabolic abnormalities mediated through inflammatory responses are fundamental in the progression of CRC. This dysregulation of essential metabolic pathways in colorectal cancer, facilitates tumor proliferation, immune evasion, and metastasis. Additionally, this review explores how inflammatory mediators, and dietary carcinogens induce metabolic alterations, fostering a pro-tumorigenic milieu. Special focus is placed on the aryl hydrocarbon receptor (AhR) as a pivotal metabolic regulator that links inflammation and tumor metabolism, elucidating its function in the reconfiguration of cellular energetics and the inflammatory microenvironment. Furthermore, this review also focuses on clarifying the relationship between inflammation, metabolic dysregulation, and the progression of CRC, so as to identify potential therapeutic targets.
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Affiliation(s)
- Jasmine Swain
- School of Biotechnology, KIIT University, Bhubaneswar, 751024, Odisha, India
- School of Applied Sciences, KIIT University, Bhubaneswar, 751024, Odisha, India
| | - Preeti
- School of Biotechnology, KIIT University, Bhubaneswar, 751024, Odisha, India
| | - Chandana Mohanty
- School of Applied Sciences, KIIT University, Bhubaneswar, 751024, Odisha, India
| | - Atul Anand Bajoria
- Kalinga Institute of Dental Sciences, KIIT University, Bhubaneswar, 751024, India
| | - Srinivas Patnaik
- School of Biotechnology, KIIT University, Bhubaneswar, 751024, Odisha, India
| | - Aoife Ward Gahlawat
- German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany
| | - Kumar Nikhil
- School of Biotechnology, KIIT University, Bhubaneswar, 751024, Odisha, India
| | - Soumya R Mohapatra
- School of Biotechnology, KIIT University, Bhubaneswar, 751024, Odisha, India.
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Lu Z, Zhang C, Zhang J, Su W, Wang G, Wang Z. The Kynurenine Pathway and Indole Pathway in Tryptophan Metabolism Influence Tumor Progression. Cancer Med 2025; 14:e70703. [PMID: 40103267 PMCID: PMC11919716 DOI: 10.1002/cam4.70703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 01/22/2025] [Accepted: 02/04/2025] [Indexed: 03/20/2025] Open
Abstract
Tryptophan (Trp), an essential amino acid, is solely acquired through dietary intake. It is vital for protein biosynthesis and acts as a precursor for numerous key bioactive compounds. The Kynurenine Pathway and the Indole Pathway are the main metabolic routes and are extensively involved in the occurrence and progression of diseases in the digestive, nervous, and urinary systems. In the Kynurenine Pathway, enzymes crucial to tryptophan metabolism, indoleamine-2,3-dioxygenase 1 (IDO1), IDO2, and Trp-2,3-dioxygenase (TDO), trigger tumor immune resistance within the tumor microenvironment and nearby lymph nodes by depleting Trp or by activating the Aromatic Hydrocarbon Receptor (AhR) through its metabolites. Furthermore, IDO1 can influence immune responses via non-enzymatic pathways. The Kynurenine Pathway exerts its effects on tumor growth through various mechanisms, including NAD+ regulation, angiogenesis promotion, tumor metastasis enhancement, and the inhibition of tumor ferroptosis. In the Indole Pathway, indole and its related metabolites are involved in gastrointestinal homeostasis, tumor immunity, and drug resistance. The gut microbiota related to indole metabolism plays a critical role in determining the effectiveness of tumor treatment strategies and can influence the efficacy of immunochemotherapy. It is worth noting that there are conflicting effects of the Kynurenine Pathway and the Indole Pathway on the same tumor phenotype. For example, different tryptophan metabolites affect the cell cycle differently, and indole metabolism has inconsistent protective effects on tumors in different regions. These differences may hold potential for enhancing therapeutic efficacy.
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Affiliation(s)
- Zhanhui Lu
- Department of Medical Oncology, Longhua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Shanghai University of Traditional Chinese MedicineShanghaiChina
- Cancer Institute, Longhua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Chengcheng Zhang
- Department of Medical Oncology, Longhua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Shanghai University of Traditional Chinese MedicineShanghaiChina
- Cancer Institute, Longhua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Jia Zhang
- Provincial Hospital Affiliated to Shandong First Medical UniversityJinanShandongChina
| | - Wan Su
- Department of Medical Oncology, Longhua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Guoying Wang
- Department of Critical Care MedicineThe Second People's Hospital of DongyingDongyingShandongChina
| | - Zhongqi Wang
- Department of Medical Oncology, Longhua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
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Xie A, Wang T, Shi W, He F, Sun X, Li P. Unveiling the Immune effects of AHR in tumors: a decade of insights from bibliometric analysis (2010-2023). Discov Oncol 2024; 15:616. [PMID: 39495340 PMCID: PMC11535112 DOI: 10.1007/s12672-024-01480-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 10/22/2024] [Indexed: 11/05/2024] Open
Abstract
BACKGROUND The Aryl Hydrocarbon Receptor (AHR) is a transcription factor that regulates several biological processes. Its potential in anti-tumor immunotherapy is becoming clearer, yet no bibliometric studies on this topic exist. This study aims to understand the current research landscape and identify future directions through a bibliometric analysis of AHR's anti-tumor immunological effects. METHODS We conducted a comprehensive bibliometric analysis of AHR antitumor immunotherapy papers in the Web of Science Core Collection. Various aspects of the publications were analyzed, and research hotspots and future trends were identified using scientific bibliometric tools and statistical methods. RESULTS We collected 592 English papers published between 2010 and 2023, with an almost annual increase. Most publications were from the USA, followed by China, Germany, and Italy. The journal "Frontiers in Immunology" had the most papers, and the most cited paper was Christiane A. Opitz's "An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor." The research is centered around AHR gene expression, with a growing focus on intestinal disease and the development of Programmed cell death ligand 1 (PD-L1) drugs. CONCLUSION This bibliometric study highlights the significance of AHR in immunomodulatory research, outlining the research trends and key contributors. It suggests AHR's immune effects may mediate the process of colitis cancer transformation, providing valuable insights for future anti-tumor immunotherapy strategies based on AHR.
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Affiliation(s)
- Anni Xie
- Anhui University of Traditional Chinese Medicine, Hefei, 230001, China
| | - Ting Wang
- Oncology Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230001, China
| | - Wenjing Shi
- Oncology Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230001, China
| | - Fang He
- Anhui University of Traditional Chinese Medicine, Hefei, 230001, China
| | - Xin Sun
- Oncology Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230001, China.
| | - Ping Li
- Anhui University of Traditional Chinese Medicine, Hefei, 230001, China.
- Oncology Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230001, China.
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Walcheck MT, Schwartz PB, Carrillo ND, Matkowskyj KA, Nukaya M, Bradfield CA, Ronnekleiv-Kelly SM. Aryl Hydrocarbon Receptor Knockout Accelerates PanIN Formation and Fibro-Inflammation in a Mutant Kras -Driven Pancreatic Cancer Model. Pancreas 2024; 53:e670-e680. [PMID: 38696422 PMCID: PMC11321943 DOI: 10.1097/mpa.0000000000002357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/04/2024]
Abstract
OBJECTIVES The pathogenesis of pancreas cancer (PDAC) remains poorly understood, hindering efforts to develop a more effective therapy for PDAC. Recent discoveries show the aryl hydrocarbon receptor (AHR) plays a crucial role in the development of several cancers and can be targeted for therapeutic effect. However, its involvement in the pathogenesis of PDAC remains unclear. To address this gap, we evaluated the role of AHR in the development of PDAC precancerous lesions in vivo . MATERIALS AND METHODS We created a global AHR-null, mutant Kras -driven PDAC mouse model (A -/- KC) and evaluated the changes in PDAC precursor lesion formation (PanIN-1, 2, and 3) and associated fibro-inflammation between KC and A -/- KC at 5 months of age. We then examined the changes in the immune microenvironment followed by single-cell RNA-sequencing analysis to evaluate concomitant transcriptomic changes. RESULTS We identified a significant increase in PanIN-1 lesion formation and PanIN-1 associated fibro-inflammatory infiltrate in A -/- KC versus KC mice. This was associated with significant changes in the adaptive immune system, particularly a decrease in the CD4+/CD8+ T-cell ratio, as well as a decrease in the T-regulatory/Th17 T-cell ratio suggesting unregulated inflammation. CONCLUSIONS These findings show the loss of AHR results in heightened Kras -induced PanIN formation, through modulation of immune cells within the pancreatic tumor microenvironment.
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Affiliation(s)
- Morgan T Walcheck
- From the Division of Surgical Oncology, Department of Surgery, University of Wisconsin School of Medicine and Public Health
| | - Patrick B Schwartz
- From the Division of Surgical Oncology, Department of Surgery, University of Wisconsin School of Medicine and Public Health
| | - Noah D Carrillo
- McArdle Laboratory for Cancer Research, University of Wisconsin
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Dai Z, Deng KL, Wang XM, Yang DX, Tang CL, Zhou YP. Bidirectional effects of the tryptophan metabolite indole-3-acetaldehyde on colorectal cancer. World J Gastrointest Oncol 2024; 16:2697-2715. [PMID: 38994159 PMCID: PMC11236226 DOI: 10.4251/wjgo.v16.i6.2697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 02/13/2024] [Accepted: 03/25/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) has a high incidence and mortality. Recent studies have shown that indole derivatives involved in gut microbiota metabolism can impact the tumorigenesis, progression, and metastasis of CRC. AIM To investigate the effect of indole-3-acetaldehyde (IAAD) on CRC. METHODS The effect of IAAD was evaluated in a syngeneic mouse model of CRC and CRC cell lines (HCT116 and DLD-1). Cell proliferation was assessed by Ki-67 fluorescence staining and cytotoxicity tests. Cell apoptosis was analysed by flow cytometry after staining with Annexin V-fluorescein isothiocyanate and propidium iodide. Invasiveness was investigated using the transwell assay. Western blotting and real-time fluorescence quantitative polymerase chain reaction were performed to evaluate the expression of epithelial-mesenchymal transition related genes and aryl hydrocarbon receptor (AhR) downstream genes. The PharmMapper, SEA, and SWISS databases were used to screen for potential target proteins of IAAD, and the core proteins were identified through the String database. RESULTS IAAD reduced tumorigenesis in a syngeneic mouse model. In CRC cell lines HCT116 and DLD1, IAAD exhibited cytotoxicity starting at 24 h of treatment, while it reduced Ki67 expression in the nucleus. The results of flow cytometry showed that IAAD induced apoptosis in HCT116 cells but had no effect on DLD1 cells, which may be related to the activation of AhR. IAAD can also increase the invasiveness and epithelial-mesenchymal transition of HCT116 and DLD1 cells. At low concentrations (< 12.5 μmol/L), IAAD only exhibited cytotoxic effects without promoting cell invasion. In addition, predictions based on online databases, protein-protein interaction analysis, and molecular docking showed that IAAD can bind to matrix metalloproteinase-9 (MMP9), angiotensin converting enzyme (ACE), poly(ADP-ribose) polymerase-1 (PARP1), matrix metalloproteinase-2 (MMP2), and myeloperoxidase (MPO). CONCLUSION Indole-3-aldehyde can induce cell apoptosis and inhibit cell proliferation to prevent the occurrence of CRC; however, at high concentrations (≥ 25 μmol/L), it can also promote epithelial-mesenchymal transition and invasion in CRC cells. IAAD activates AhR and directly binds MMP9, ACE, PARP1, MMP2, and MPO, which partly reveals why it has a bidirectional effect.
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Affiliation(s)
- Ze Dai
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
| | - Kai-Li Deng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xiao-Mei Wang
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
| | - Dong-Xue Yang
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Institute of Digestive Disease of Ningbo University, Ningbo University, Ningbo 315020, Zhejiang Province, China
- Ningbo Key Laboratory of Translational Medicine Research on Gastroenterology and Hepatology, Ningbo Key Laboratory, Ningbo 315020, Zhejiang Province, China
| | - Chun-Lan Tang
- Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
| | - Yu-Ping Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Institute of Digestive Disease of Ningbo University, Ningbo University, Ningbo 315020, Zhejiang Province, China
- Ningbo Key Laboratory of Translational Medicine Research on Gastroenterology and Hepatology, Ningbo Key Laboratory, Ningbo 315020, Zhejiang Province, China
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Dai Z, Deng KL, Wang XM, Yang DX, Tang CL, Zhou YP. Bidirectional effects of the tryptophan metabolite indole-3-acetaldehyde on colorectal cancer. World J Gastrointest Oncol 2024; 16:2685-2703. [DOI: 10.4251/wjgo.v16.i6.2685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 02/13/2024] [Accepted: 03/25/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) has a high incidence and mortality. Recent studies have shown that indole derivatives involved in gut microbiota metabolism can impact the tumorigenesis, progression, and metastasis of CRC.
AIM To investigate the effect of indole-3-acetaldehyde (IAAD) on CRC.
METHODS The effect of IAAD was evaluated in a syngeneic mouse model of CRC and CRC cell lines (HCT116 and DLD-1). Cell proliferation was assessed by Ki-67 fluorescence staining and cytotoxicity tests. Cell apoptosis was analysed by flow cytometry after staining with Annexin V-fluorescein isothiocyanate and propidium iodide. Invasiveness was investigated using the transwell assay. Western blotting and real-time fluorescence quantitative polymerase chain reaction were performed to evaluate the expression of epithelial-mesenchymal transition related genes and aryl hydrocarbon receptor (AhR) downstream genes. The PharmMapper, SEA, and SWISS databases were used to screen for potential target proteins of IAAD, and the core proteins were identified through the String database.
RESULTS IAAD reduced tumorigenesis in a syngeneic mouse model. In CRC cell lines HCT116 and DLD1, IAAD exhibited cytotoxicity starting at 24 h of treatment, while it reduced Ki67 expression in the nucleus. The results of flow cytometry showed that IAAD induced apoptosis in HCT116 cells but had no effect on DLD1 cells, which may be related to the activation of AhR. IAAD can also increase the invasiveness and epithelial-mesenchymal transition of HCT116 and DLD1 cells. At low concentrations (< 12.5 μmol/L), IAAD only exhibited cytotoxic effects without promoting cell invasion. In addition, predictions based on online databases, protein-protein interaction analysis, and molecular docking showed that IAAD can bind to matrix metalloproteinase-9 (MMP9), angiotensin converting enzyme (ACE), poly(ADP-ribose) polymerase-1 (PARP1), matrix metalloproteinase-2 (MMP2), and myeloperoxidase (MPO).
CONCLUSION Indole-3-aldehyde can induce cell apoptosis and inhibit cell proliferation to prevent the occurrence of CRC; however, at high concentrations (≥ 25 μmol/L), it can also promote epithelial-mesenchymal transition and invasion in CRC cells. IAAD activates AhR and directly binds MMP9, ACE, PARP1, MMP2, and MPO, which partly reveals why it has a bidirectional effect.
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Affiliation(s)
- Ze Dai
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
| | - Kai-Li Deng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xiao-Mei Wang
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
| | - Dong-Xue Yang
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Institute of Digestive Disease of Ningbo University, Ningbo University, Ningbo 315020, Zhejiang Province, China
- Ningbo Key Laboratory of Translational Medicine Research on Gastroenterology and Hepatology, Ningbo Key Laboratory, Ningbo 315020, Zhejiang Province, China
| | - Chun-Lan Tang
- Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
| | - Yu-Ping Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Institute of Digestive Disease of Ningbo University, Ningbo University, Ningbo 315020, Zhejiang Province, China
- Ningbo Key Laboratory of Translational Medicine Research on Gastroenterology and Hepatology, Ningbo Key Laboratory, Ningbo 315020, Zhejiang Province, China
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Congues F, Wang P, Lee J, Lin D, Shahid A, Xie J, Huang Y. Targeting aryl hydrocarbon receptor to prevent cancer in barrier organs. Biochem Pharmacol 2024; 223:116156. [PMID: 38518996 PMCID: PMC11144369 DOI: 10.1016/j.bcp.2024.116156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 03/08/2024] [Accepted: 03/19/2024] [Indexed: 03/24/2024]
Abstract
The skin, lung, and gut are important barrier organs that control how the body reacts to environmental stressors such as ultraviolet (UV) radiation, air pollutants, dietary components, and microorganisms. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that plays an important role in maintaining homeostasis of barrier organs. AhR was initially discovered as a receptor for environmental chemical carcinogens such as polycyclic aromatic hydrocarbons (PAHs). Activation of AhR pathways by PAHs leads to increased DNA damage and mutations which ultimately lead to carcinogenesis. Ongoing evidence reveals an ever-expanding role of AhR. Recently, AhR has been linked to immune systems by the interaction with the development of natural killer (NK) cells, regulatory T (Treg) cells, and T helper 17 (Th17) cells, as well as the production of immunosuppressive cytokines. However, the role of AhR in carcinogenesis is not as straightforward as we initially thought. Although AhR activation has been shown to promote carcinogenesis in some studies, others suggest that it may act as a tumor suppressor. In this review, we aim to explore the role of AhR in the development of cancer that originates from barrier organs. We also examined the preclinical efficacy data of AhR agonists and antagonists on carcinogenesis to determine whether AhR modulation can be a viable option for cancer chemoprevention.
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Affiliation(s)
- Francoise Congues
- Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Pengcheng Wang
- Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA; Department of Stomatology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Joshua Lee
- Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Daphne Lin
- Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Ayaz Shahid
- Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Jianming Xie
- Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Ying Huang
- Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA.
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Shen AL, Moran SM, Glover EN, Lin BC, Carney PR, Bradfield CA. Familial isolated pituitary adenoma is independent of Ahr genotype in a novel mouse model of disease. Heliyon 2024; 10:e28231. [PMID: 38590848 PMCID: PMC10999881 DOI: 10.1016/j.heliyon.2024.e28231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 03/13/2024] [Accepted: 03/13/2024] [Indexed: 04/10/2024] Open
Abstract
Human familial isolated pituitary adenoma (FIPA) has been linked to germline heterozygous mutations in the gene encoding the aryl hydrocarbon receptor-interacting protein (AIP, also known as ARA9, XAP2, FKBP16, or FKBP37). To investigate the hypothesis that AIP is a pituitary adenoma tumor suppressor via its role in aryl hydrocarbon receptor (AHR) signaling, we have compared the pituitary phenotype of our global null Aip (AipΔC) mouse model with that of a conditional null Aip model (Aipfx/fx) carrying the same deletion, as well as pituitary phenotypes of Ahr global null and Arnt conditional null animals. We demonstrate that germline AipΔC heterozygosity results in a high incidence of pituitary tumors in both sexes, primarily somatotropinomas, at 16 months of age. Biallelic deletion of Aip in Pit-1 cells (Aipfx/fx:rGHRHRcre) increased pituitary tumor incidence and also accelerated tumor progression, supporting a loss-of-function/loss-of-heterozygosity model of tumorigenesis. Tumor development exhibited sexual dimorphism in wildtype and Aipfx/fx:rGHRHRcre animals. Despite the role of AHR as a tumor suppressor in other cancers, the observation that animals lacking AHR in all tissues, or ARNT in Pit-1 cells, do not develop somatotropinomas argues against the hypothesis that pituitary tumorigenesis in AIP-associated FIPA is related to decreased activities of either the Ahr or Arnt gene products.
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Affiliation(s)
- Anna L Shen
- The McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53706, United States
| | - Susan M Moran
- The McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53706, United States
| | - Edward N Glover
- The McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53706, United States
| | - Bernice C Lin
- The McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53706, United States
- Current address, Lin-Zhi International, 2945, Oakmead Village Court, Santa Clara, CA, 95051, United States
| | - Patrick R Carney
- The McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53706, United States
- Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53706, United States
| | - Christopher A Bradfield
- The McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53706, United States
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Glatt H, Weißenberg SY, Ehlers A, Lampen A, Seidel A, Schumacher F, Engst W, Meinl W. Formation of DNA Adducts by 1-Methoxy-3-indolylmethylalcohol, a Breakdown Product of a Glucosinolate, in the Mouse: Impact of the SULT1A1 Status-Wild-Type, Knockout or Humanised. Int J Mol Sci 2024; 25:3824. [PMID: 38612635 PMCID: PMC11012018 DOI: 10.3390/ijms25073824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 03/20/2024] [Accepted: 03/22/2024] [Indexed: 04/14/2024] Open
Abstract
We previously found that feeding rats with broccoli or cauliflower leads to the formation of characteristic DNA adducts in the liver, intestine and various other tissues. We identified the critical substances in the plants as 1-methoxy-3-indolylmethyl (1-MIM) glucosinolate and its degradation product 1-MIM-OH. DNA adduct formation and the mutagenicity of 1-MIM-OH in cell models were drastically enhanced when human sulfotransferase (SULT) 1A1 was expressed. The aim of this study was to clarify the role of SULT1A1 in DNA adduct formation by 1-MIM-OH in mouse tissues in vivo. Furthermore, we compared the endogenous mouse Sult1a1 and transgenic human SULT1A1 in the activation of 1-MIM-OH using genetically modified mouse strains. We orally treated male wild-type (wt) and Sult1a1-knockout (ko) mice, as well as corresponding lines carrying the human SULT1A1-SULT1A2 gene cluster (tg and ko-tg), with 1-MIM-OH. N2-(1-MIM)-dG and N6-(1-MIM)-dA adducts in DNA were analysed using isotope-dilution UPLC-MS/MS. In the liver, caecum and colon adducts were abundant in mice expressing mouse and/or human SULT1A1, but were drastically reduced in ko mice (1.2-10.6% of wt). In the kidney and small intestine, adduct levels were high in mice carrying human SULT1A1-SULT1A2 genes, but low in wt and ko mice (1.8-6.3% of tg-ko). In bone marrow, adduct levels were very low, independently of the SULT1A1 status. In the stomach, they were high in all four lines. Thus, adduct formation was primarily controlled by SULT1A1 in five out of seven tissues studied, with a strong impact of differences in the tissue distribution of mouse and human SULT1A1. The behaviour of 1-MIM-OH in these models (levels and tissue distribution of DNA adducts; impact of SULTs) was similar to that of methyleugenol, classified as "probably carcinogenic to humans". Thus, there is a need to test 1-MIM-OH for carcinogenicity in animal models and to study its adduct formation in humans consuming brassicaceous foodstuff.
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Affiliation(s)
- Hansruedi Glatt
- Department Food Safety, Federal Institute of Risk Assessment (BfR), Max-Dohrn-Strasse 8–10, 10589 Berlin, Germany; (S.Y.W.); (A.E.); (A.L.)
- Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114–116, 14558 Nuthetal, Germany; (F.S.); (W.E.); (W.M.)
| | - Sarah Yasmin Weißenberg
- Department Food Safety, Federal Institute of Risk Assessment (BfR), Max-Dohrn-Strasse 8–10, 10589 Berlin, Germany; (S.Y.W.); (A.E.); (A.L.)
| | - Anke Ehlers
- Department Food Safety, Federal Institute of Risk Assessment (BfR), Max-Dohrn-Strasse 8–10, 10589 Berlin, Germany; (S.Y.W.); (A.E.); (A.L.)
| | - Alfonso Lampen
- Department Food Safety, Federal Institute of Risk Assessment (BfR), Max-Dohrn-Strasse 8–10, 10589 Berlin, Germany; (S.Y.W.); (A.E.); (A.L.)
| | - Albrecht Seidel
- Biochemical Institute for Environmental Carcinogens (BIU), Prof. Dr. Gernot Grimmer-Foundation, Lurup 4, 22927 Grosshansdorf, Germany;
| | - Fabian Schumacher
- Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114–116, 14558 Nuthetal, Germany; (F.S.); (W.E.); (W.M.)
- Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Strasse 2–4, 14195 Berlin, Germany
| | - Wolfram Engst
- Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114–116, 14558 Nuthetal, Germany; (F.S.); (W.E.); (W.M.)
| | - Walter Meinl
- Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114–116, 14558 Nuthetal, Germany; (F.S.); (W.E.); (W.M.)
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11
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Griffith BD, Frankel TL. The Aryl Hydrocarbon Receptor: Impact on the Tumor Immune Microenvironment and Modulation as a Potential Therapy. Cancers (Basel) 2024; 16:472. [PMID: 38339226 PMCID: PMC10854841 DOI: 10.3390/cancers16030472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/18/2024] [Accepted: 01/21/2024] [Indexed: 02/12/2024] Open
Abstract
The aryl hydrocarbon receptor (AhR) is a ubiquitous nuclear receptor with a broad range of functions, both in tumor cells and immune cells within the tumor microenvironment (TME). Activation of AhR has been shown to have a carcinogenic effect in a variety of organs, through induction of cellular proliferation and migration, promotion of epithelial-to-mesenchymal transition, and inhibition of apoptosis, among other functions. However, the impact on immune cell function is more complicated, with both pro- and anti-tumorigenic roles identified. Although targeting AhR in cancer has shown significant promise in pre-clinical studies, there has been limited efficacy in phase III clinical trials to date. With the contrasting roles of AhR activation on immune cell polarization, understanding the impact of AhR activation on the tumor immune microenvironment is necessary to guide therapies targeting the AhR. This review article summarizes the state of knowledge of AhR activation on the TME, limitations of current findings, and the potential for modulation of the AhR as a cancer therapy.
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Affiliation(s)
- Brian D. Griffith
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Timothy L. Frankel
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA;
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
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12
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Wan T, Wang Y, He K, Zhu S. Microbial sensing in the intestine. Protein Cell 2023; 14:824-860. [PMID: 37191444 PMCID: PMC10636641 DOI: 10.1093/procel/pwad028] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 05/04/2023] [Indexed: 05/17/2023] Open
Abstract
The gut microbiota plays a key role in host health and disease, particularly through their interactions with the immune system. Intestinal homeostasis is dependent on the symbiotic relationships between the host and the diverse gut microbiota, which is influenced by the highly co-evolved immune-microbiota interactions. The first step of the interaction between the host and the gut microbiota is the sensing of the gut microbes by the host immune system. In this review, we describe the cells of the host immune system and the proteins that sense the components and metabolites of the gut microbes. We further highlight the essential roles of pattern recognition receptors (PRRs), the G protein-coupled receptors (GPCRs), aryl hydrocarbon receptor (AHR) and the nuclear receptors expressed in the intestinal epithelial cells (IECs) and the intestine-resident immune cells. We also discuss the mechanisms by which the disruption of microbial sensing because of genetic or environmental factors causes human diseases such as the inflammatory bowel disease (IBD).
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Affiliation(s)
- Tingting Wan
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Yalong Wang
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Kaixin He
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Shu Zhu
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
- Department of Digestive Disease, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China
- Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China
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13
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Liu S, Yan W, Lv Q, Yang L, Miao Y, Hu Y, Wei Z. 3, 3'-diindolylmethane, a natural aryl hydrocarbon receptor agonist, alleviates ulcerative colitis by enhancing "glycolysis-lactate-STAT3″ and TIP60 signals-mediated Treg differentiation. Mol Immunol 2023; 163:147-162. [PMID: 37793204 DOI: 10.1016/j.molimm.2023.09.009] [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: 03/29/2023] [Revised: 07/26/2023] [Accepted: 09/14/2023] [Indexed: 10/06/2023]
Abstract
BACKGROUND Aryl hydrocarbon receptor (AhR) plays an important role in the occurrence and development of ulcerative colitis (UC). In this study, the effect and mechanism of 3, 3'-diindolylmethane (DIM), the classical AhR agonist, on UC was investigated from the angle of recovering the balance of Th17/Treg. METHODS The in vivo colitis model was established in mice by using dextran sulfate sodium, and CD4+ T cells were used to simulate the in vitro differentiation of Treg and Th17 cells. The proportions and related factors of Th17 and Treg cells were measured using flow cytometry, Q-PCR and western blotting. The glycolysis was evaluated by examining the glucose uptake, glucose consumption and lactate production using kits or immunofluorescence. The activation of AhR was detected by western blotting and the XRE-luciferase reporter gene. The co-immunoprecipitation, transfection or other methods were selected to investigate and identify the signaling molecular pathway. RESULTS DIM significantly attenuated symptoms of colitis mice by rebuilding the balance of Th17/Treg in anoxic colons. In hypoxia, a more potent promotion of Treg differentiation was showed by DIM relative to normoxia, and siFoxp3 prevented DIM-suppressed Th17 differentiation. DIM repressed the excessive glycolysis in hypoxia evidenced by down-regulated glucose uptake, lactate production, Glut1 and HK2 levels. Interestingly, IL-10, the function-related factor of Treg cells, showed the feedback effect of DIM-suppressed glycolysis. Besides, 2-deoxy-D-glucose, HK2 plasmid and IL-10 antibody prevented increase of DIM on the expression of Foxp3 at the transcriptional level and subsequent Treg differentiation through the lactate-STAT3 pathway, and reasons for the direct improvement of DIM on Foxp3 protein was attributed to promoting the formation of HIF-1α/TIP60 complexes as well as subsequent acetylation and protein stability. Finally, AhR dependence and mechanisms for DIM-improved Treg differentiation in vitro and in vivo were well confirmed by using plasmids or inhibitors. CONCLUSIONS DIM enhances activation of AhR and subsequent "glycolysis-lactate-STAT3″ and TIP60 signals-mediated Treg differentiation.
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Affiliation(s)
- Shukun Liu
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
| | - Wenxin Yan
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
| | - Qi Lv
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
| | - Ling Yang
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
| | - Yumeng Miao
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
| | - Yuxiao Hu
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
| | - Zhifeng Wei
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
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14
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Hou JJ, Ma AH, Qin YH. Activation of the aryl hydrocarbon receptor in inflammatory bowel disease: insights from gut microbiota. Front Cell Infect Microbiol 2023; 13:1279172. [PMID: 37942478 PMCID: PMC10628454 DOI: 10.3389/fcimb.2023.1279172] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 10/09/2023] [Indexed: 11/10/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disease that affects more than 3.5 million people, with rising prevalence. It deeply affects patients' daily life, increasing the burden on patients, families, and society. Presently, the etiology of IBD remains incompletely clarified, while emerging evidence has demonstrated that altered gut microbiota and decreased aryl hydrocarbon receptor (AHR) activity are closely associated with IBD. Furthermore, microbial metabolites are capable of AHR activation as AHR ligands, while the AHR, in turn, affects the microbiota through various pathways. In light of the complex connection among gut microbiota, the AHR, and IBD, it is urgent to review the latest research progress in this field. In this review, we describe the role of gut microbiota and AHR activation in IBD and discussed the crosstalk between gut microbiota and the AHR in the context of IBD. Taken as a whole, we propose new therapeutic strategies targeting the AHR-microbiota axis for IBD, even for other related diseases caused by AHR-microbiota dysbiosis.
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Affiliation(s)
| | | | - Yue-Hua Qin
- Department of Gastroenterology, Shaoxing People’s Hospital, Shaoxing, China
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15
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Vázquez-Gómez G, Petráš J, Dvořák Z, Vondráček J. Aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) play both distinct and common roles in the regulation of colon homeostasis and intestinal carcinogenesis. Biochem Pharmacol 2023; 216:115797. [PMID: 37696457 DOI: 10.1016/j.bcp.2023.115797] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 09/07/2023] [Accepted: 09/08/2023] [Indexed: 09/13/2023]
Abstract
Both aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) belong among key regulators of xenobiotic metabolism in the intestinal tissue. AhR in particular is activated by a wide range of environmental and dietary carcinogens. The data accumulated over the last two decades suggest that both of these transcriptional regulators play a much wider role in the maintenance of gut homeostasis, and that both transcription factors may affect processes linked with intestinal tumorigenesis. Intestinal epithelium is continuously exposed to a wide range of AhR, PXR and dual AhR/PXR ligands formed by intestinal microbiota or originating from diet. Current evidence suggests that specific ligands of both AhR and PXR can protect intestinal epithelium against inflammation and assist in the maintenance of epithelial barrier integrity. AhR, and to a lesser extent also PXR, have been shown to play a protective role against inflammation-induced colon cancer, or, in mouse models employing overactivation of Wnt/β-catenin signaling. In contrast, other evidence suggests that both receptors may contribute to modulation of transformed colon cell behavior, with a potential to promote cancer progression and/or chemoresistance. The review focuses on both overlapping and separate roles of the two receptors in these processes, and on possible implications of their activity within the context of intestinal tissue.
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Affiliation(s)
- Gerardo Vázquez-Gómez
- Department of Cytokinetics, Institute of Biophysics of the CAS, Královopolská 135, 61265 Brno, Czech Republic
| | - Jiří Petráš
- Department of Cytokinetics, Institute of Biophysics of the CAS, Královopolská 135, 61265 Brno, Czech Republic; Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic
| | - Zdeněk Dvořák
- Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
| | - Jan Vondráček
- Department of Cytokinetics, Institute of Biophysics of the CAS, Královopolská 135, 61265 Brno, Czech Republic.
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16
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Bartkeviciene A, Jasukaitiene A, Zievyte I, Stukas D, Ivanauskiene S, Urboniene D, Maimets T, Jaudzems K, Vitkauskiene A, Matthews J, Dambrauskas Z, Gulbinas A. Association between AHR Expression and Immune Dysregulation in Pancreatic Ductal Adenocarcinoma: Insights from Comprehensive Immune Profiling of Peripheral Blood Mononuclear Cells. Cancers (Basel) 2023; 15:4639. [PMID: 37760608 PMCID: PMC10526859 DOI: 10.3390/cancers15184639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 09/15/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), has an immune suppressive environment that allows tumour cells to evade the immune system. The aryl-hydrocarbon receptor (AHR) is a transcription factor that can be activated by certain exo/endo ligands, including kynurenine (KYN) and other tryptophan metabolites. Once activated, AHR regulates the expression of various genes involved in immune responses and inflammation. Previous studies have shown that AHR activation in PDAC can have both pro-tumorigenic and anti-tumorigenic effects, depending on the context. It can promote tumour growth and immune evasion by suppressing anti-tumour immune responses or induce anti-tumour effects by enhancing immune cell function. In this study involving 30 PDAC patients and 30 healthy individuals, peripheral blood samples were analysed. PDAC patients were categorized into Low (12 patients) and High/Medium (18 patients) AHR groups based on gene expression in peripheral blood mononuclear cells (PBMCs). The Low AHR group showed distinct immune characteristics, including increased levels of immune-suppressive proteins such as PDL1, as well as alterations in lymphocyte and monocyte subtypes. Functional assays demonstrated changes in phagocytosis, nitric oxide production, and the expression of cytokines IL-1, IL-6, and IL-10. These findings indicate that AHR's expression level has a crucial role in immune dysregulation in PDAC and could be a potential target for early diagnostics and personalised therapeutics.
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Affiliation(s)
- Arenida Bartkeviciene
- Laboratory of Surgical Gastroenterology, Institute for Digestive Research, Lithuanian University of Health Sciences, Eiveniu 4, 50103 Kaunas, Lithuania; (A.J.); (I.Z.); (D.S.); (S.I.); (Z.D.); (A.G.)
| | - Aldona Jasukaitiene
- Laboratory of Surgical Gastroenterology, Institute for Digestive Research, Lithuanian University of Health Sciences, Eiveniu 4, 50103 Kaunas, Lithuania; (A.J.); (I.Z.); (D.S.); (S.I.); (Z.D.); (A.G.)
| | - Inga Zievyte
- Laboratory of Surgical Gastroenterology, Institute for Digestive Research, Lithuanian University of Health Sciences, Eiveniu 4, 50103 Kaunas, Lithuania; (A.J.); (I.Z.); (D.S.); (S.I.); (Z.D.); (A.G.)
| | - Darius Stukas
- Laboratory of Surgical Gastroenterology, Institute for Digestive Research, Lithuanian University of Health Sciences, Eiveniu 4, 50103 Kaunas, Lithuania; (A.J.); (I.Z.); (D.S.); (S.I.); (Z.D.); (A.G.)
| | - Sandra Ivanauskiene
- Laboratory of Surgical Gastroenterology, Institute for Digestive Research, Lithuanian University of Health Sciences, Eiveniu 4, 50103 Kaunas, Lithuania; (A.J.); (I.Z.); (D.S.); (S.I.); (Z.D.); (A.G.)
| | - Daiva Urboniene
- Department of Laboratory Medicine, Lithuanian University of Health Sciences, Eiveniu 4, 50103 Kaunas, Lithuania; (D.U.); (A.V.)
| | - Toivo Maimets
- Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010 Tartu, Estonia;
| | - Kristaps Jaudzems
- Department of Physical Organic Chemistry, Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia;
| | - Astra Vitkauskiene
- Department of Laboratory Medicine, Lithuanian University of Health Sciences, Eiveniu 4, 50103 Kaunas, Lithuania; (D.U.); (A.V.)
| | - Jason Matthews
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 1046 Blindern, 0317 Oslo, Norway;
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Zilvinas Dambrauskas
- Laboratory of Surgical Gastroenterology, Institute for Digestive Research, Lithuanian University of Health Sciences, Eiveniu 4, 50103 Kaunas, Lithuania; (A.J.); (I.Z.); (D.S.); (S.I.); (Z.D.); (A.G.)
| | - Antanas Gulbinas
- Laboratory of Surgical Gastroenterology, Institute for Digestive Research, Lithuanian University of Health Sciences, Eiveniu 4, 50103 Kaunas, Lithuania; (A.J.); (I.Z.); (D.S.); (S.I.); (Z.D.); (A.G.)
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17
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Sládeková L, Zgarbová E, Vrzal R, Vanda D, Soural M, Jakubcová K, Vázquez-Gómez G, Vondráček J, Dvořák Z. Switching on/off aryl hydrocarbon receptor and pregnane X receptor activities by chemically modified tryptamines. Toxicol Lett 2023; 387:63-75. [PMID: 37778463 DOI: 10.1016/j.toxlet.2023.09.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 09/01/2023] [Accepted: 09/27/2023] [Indexed: 10/03/2023]
Abstract
Microbial indoles have been demonstrated as selective or dual agonists and ligands of the pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR). However, structural determinants of microbial indoles selectivity towards both receptors remain elusive. Here, we studied the effects of existing and newly synthesized derivatives of indole microbial metabolite tryptamine on the activity of AhR and PXR receptors. We show that the elongation of indolyl-3-alkaneamine chain, indole N-methylation and conversion of indolyl-3-alkaneamines to oleamides resulted in a major increase of PXR activity and in parallel loss of AhR activity. Using reporter gene assays, RT-PCR and TR-FRET techniques, we have characterized in detail the activation of PXR by novel indolyl-3-alkanyl-oleamides, 1-methyltryptamine and 1-methyltryptamine-acetamide. As a proof of concept, we demonstrated anti-inflammatory and epithelial barrier-protective activity of lead derivatives in intestinal Caco-2 cells, employing the measurement of expression of pro-inflammatory chemokines, tight junction genes, trans-epithelial electric resistance TEER, and dextran-FITC permeability assay. In conclusion, we show that a subtle chemical modifications of simple microbial indole metabolite tryptamine, leads to substantial changes in AhR and PXR agonist activities.
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Affiliation(s)
- Lucia Sládeková
- Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
| | - Eliška Zgarbová
- Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
| | - Radim Vrzal
- Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
| | - David Vanda
- Department of Organic Chemistry, Faculty of Science, Palacký University, 17. Listopadu 12, 771 46 Olomouc, Czech Republic
| | - Miroslav Soural
- Department of Organic Chemistry, Faculty of Science, Palacký University, 17. Listopadu 12, 771 46 Olomouc, Czech Republic
| | - Klára Jakubcová
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, 612 65 Brno, Czech Republic
| | - Gerardo Vázquez-Gómez
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, 612 65 Brno, Czech Republic
| | - Jan Vondráček
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, 612 65 Brno, Czech Republic
| | - Zdeněk Dvořák
- Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic.
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18
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Reyes-Hernández OD, Figueroa-González G, Quintas-Granados LI, Gutiérrez-Ruíz SC, Hernández-Parra H, Romero-Montero A, Del Prado-Audelo ML, Bernal-Chavez SA, Cortés H, Peña-Corona SI, Kiyekbayeva L, Ateşşahin DA, Goloshvili T, Leyva-Gómez G, Sharifi-Rad J. 3,3'-Diindolylmethane and indole-3-carbinol: potential therapeutic molecules for cancer chemoprevention and treatment via regulating cellular signaling pathways. Cancer Cell Int 2023; 23:180. [PMID: 37633886 PMCID: PMC10464192 DOI: 10.1186/s12935-023-03031-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 08/13/2023] [Indexed: 08/28/2023] Open
Abstract
Dietary compounds in cancer prevention have gained significant consideration as a viable method. Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) are heterocyclic and bioactive chemicals found in cruciferous vegetables like broccoli, cauliflower, cabbage, and brussels sprouts. They are synthesized after glycolysis from the glucosinolate structure. Clinical and preclinical trials have evaluated the pharmacokinetic/pharmacodynamic, effectiveness, antioxidant, cancer-preventing (cervical dysplasia, prostate cancer, breast cancer), and anti-tumor activities of I3C and DIM involved with polyphenolic derivatives created in the digestion showing promising results. However, the exact mechanism by which they exert anti-cancer and apoptosis-inducing properties has yet to be entirely understood. Via this study, we update the existing knowledge of the state of anti-cancer investigation concerning I3C and DIM chemicals. We have also summarized; (i) the recent advancements in the use of I3C/DIM as therapeutic molecules since they represent potentially appealing anti-cancer agents, (ii) the available literature on the I3C and DIM characterization, and the challenges related to pharmacologic properties such as low solubility, and poor bioavailability, (iii) the synthesis and semi-synthetic derivatives, (iv) the mechanism of anti-tumor action in vitro/in vivo, (v) the action in cellular signaling pathways related to the regulation of apoptosis and anoikis as well as the cell cycle progression and cell proliferation such as peroxisome proliferator-activated receptor and PPARγ agonists; SR13668, Akt inhibitor, cyclins regulation, ER-dependent-independent pathways, and their current medical applications, to recognize research opportunities to potentially use these compounds instead chemotherapeutic synthetic drugs.
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Affiliation(s)
- Octavio Daniel Reyes-Hernández
- Laboratorio de Biología Molecular del Cáncer, Facultad de Estudios Superiores Zaragoza, UMIEZ, Universidad Nacional Autónoma de México, Ciudad de México, 09230, Mexico
| | - Gabriela Figueroa-González
- Laboratorio de Farmacogenética, Facultad de Estudios Superiores Zaragoza, UMIEZ, Universidad Nacional Autónoma de México, Ciudad de México, 09230, Mexico
| | | | | | - Hector Hernández-Parra
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, 04510, Mexico
| | - Alejandra Romero-Montero
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, 04510, Mexico
| | - María Luisa Del Prado-Audelo
- Escuela de Ingeniería y Ciencias, Tecnologico de Monterrey, Campus Ciudad de México, C. Puente 222, Ciudad de México, 14380, Mexico
| | - Sergio Alberto Bernal-Chavez
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, 04510, Mexico
| | - Hernán Cortés
- Laboratorio de Medicina Genómica, Departamento de Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Ciudad de Mexico, Mexico
| | - Sheila I Peña-Corona
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, 04510, Mexico
| | - Lashyn Kiyekbayeva
- Pharmaceutical School, Department of Pharmaceutical Technology, Asfendiyarov Kazakh National Medical University, Almaty, Kazakhstan
- Faculties of Pharmacy, Public Health and Nursing, Kazakh-Russian Medical University, Almaty, Kazakhstan
| | - Dilek Arslan Ateşşahin
- Baskil Vocational School, Department of Plant and Animal Production, Fırat University, Elazıg, 23100, Turkey
| | - Tamar Goloshvili
- Department of Plant Physiology and Genetic Resources, Institute of Botany, Ilia State University, Tbilisi, 0162, Georgia
| | - Gerardo Leyva-Gómez
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, 04510, Mexico.
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19
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Gu C, Tang L, Hao Y, Dong S, Shen J, Xie F, Han Z, Luo W, He J, Yu L. Network pharmacology and bioinformatics were used to construct a prognostic model and immunoassay of core target genes in the combination of quercetin and kaempferol in the treatment of colorectal cancer. J Cancer 2023; 14:1956-1980. [PMID: 37497415 PMCID: PMC10367918 DOI: 10.7150/jca.85517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Accepted: 06/18/2023] [Indexed: 07/28/2023] Open
Abstract
Purpose: CRC is a malignant tumor seriously threatening human health. Quercetin and kaempferol are representative components of traditional Chinese medicine (TCM). Previous studies have shown that both quercetin and kaempferol have antitumor pharmacological effects, nevertheless, the underlying mechanism of action remains unclear. To explore the synergy and mechanism of quercetin and kaempferol in colorectal cancer. Methods: In this study, network pharmacology, and bioinformatics are used to obtain the intersection of drug targets and disease genes. Training gene sets were acquired from the TCGA database, acquired prognostic-related genes by univariate Cox, multivariate Cox, and Lasso-Cox regression models, and validated in the GEO dataset. We also made predictions of the immune function of the samples and used molecular docking to map a model for binding two components to prognostic genes. Results: Through Lasso-Cox regression analysis, we obtained three models of drug target genes. This model predicts the combined role of quercetin and kaempferol in the treatment and prognosis of CRC. Prognostic genes are correlated with immune checkpoints and immune infiltration and play an adjuvant role in the immunotherapy of CRC. Conclusion: Core genes are regulated by quercetin and kaempferol to improve the patient's immune system and thus assist in the treatment of CRC.
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Affiliation(s)
- Chenqiong Gu
- Department of Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, P. R. China
- Central Laboratory of Panyu Central Hospital, Guangzhou, 511400, Guangdong, P.R. China
| | - LinDong Tang
- Department of Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, P. R. China
| | - Yinghui Hao
- Department of Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, P. R. China
- Central Laboratory of Panyu Central Hospital, Guangzhou, 511400, Guangdong, P.R. China
| | - Shanshan Dong
- Department of Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, P. R. China
| | - Jian Shen
- Central Laboratory of Panyu Central Hospital, Guangzhou, 511400, Guangdong, P.R. China
| | - FangMei Xie
- Central Laboratory of Panyu Central Hospital, Guangzhou, 511400, Guangdong, P.R. China
| | - ZePing Han
- Central Laboratory of Panyu Central Hospital, Guangzhou, 511400, Guangdong, P.R. China
| | - WenFeng Luo
- Central Laboratory of Panyu Central Hospital, Guangzhou, 511400, Guangdong, P.R. China
| | - JinHua He
- Central Laboratory of Panyu Central Hospital, Guangzhou, 511400, Guangdong, P.R. China
| | - Li Yu
- Department of Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, P. R. China
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20
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Zhou L, Jiang Z, Zhang Z, Xing J, Wang D, Tang D. Progress of gut microbiome and its metabolomics in early screening of colorectal cancer. Clin Transl Oncol 2023; 25:1949-1962. [PMID: 36790675 DOI: 10.1007/s12094-023-03097-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 01/18/2023] [Indexed: 02/16/2023]
Abstract
Gut microbes are widely considered to be closely associated with colorectal cancer (CRC) development. The microbiota is regarded as a potential identifier of CRC, as several studies have found great significant changes in CRC patients' microbiota and metabolic groups. Changes in microbiota, like Fusobacterium nucleatum and Bacteroides fragilis, also alter the metabolic activity of the host, promoting CRC development. In contrast, the metabolome is an intuitive discriminative biomarker as a small molecular bridge to distinguish CRC from healthy individuals due to the direct action of microbes on the host. More diagnostic microbial markers have been found, and the potential discriminatory power of microorganisms in CRC has been investigated through the combined use of biomic genomic metabolomics, bringing new ideas for screening fecal microbial markers. In this paper, we discuss the potential of microorganisms and their metabolites as biomarkers in CRC screening, hoping to provide thoughts and references for non-invasive screening of CRC.
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Affiliation(s)
- Lujia Zhou
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, 225000, People's Republic of China
| | - Zhengting Jiang
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, 225000, People's Republic of China
| | - Zhilin Zhang
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, 225000, People's Republic of China
| | - Juan Xing
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, 225000, People's Republic of China
| | - Daorong Wang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou, 225000, People's Republic of China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou, 225000, People's Republic of China.
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21
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Chen Y, Wang Y, Fu Y, Yin Y, Xu K. Modulating AHR function offers exciting therapeutic potential in gut immunity and inflammation. Cell Biosci 2023; 13:85. [PMID: 37179416 PMCID: PMC10182712 DOI: 10.1186/s13578-023-01046-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023] Open
Abstract
Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a classical exogenous synthetic ligand of AHR that has significant immunotoxic effects. Activation of AHR has beneficial effects on intestinal immune responses, but inactivation or overactivation of AHR can lead to intestinal immune dysregulation and even intestinal diseases. Sustained potent activation of AHR by TCDD results in impairment of the intestinal epithelial barrier. However, currently, AHR research has been more focused on elucidating physiologic AHR function than on dioxin toxicity. The appropriate level of AHR activation plays a role in maintaining gut health and protecting against intestinal inflammation. Therefore, AHR offers a crucial target to modulate intestinal immunity and inflammation. Herein, we summarize our current understanding of the relationship between AHR and intestinal immunity, the ways in which AHR affects intestinal immunity and inflammation, the effects of AHR activity on intestinal immunity and inflammation, and the effect of dietary habits on intestinal health through AHR. Finally, we discuss the therapeutic role of AHR in maintaining gut homeostasis and relieving inflammation.
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Affiliation(s)
- Yue Chen
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450000, China
| | - Yadong Wang
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
| | - Yawei Fu
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450000, China
| | - Yulong Yin
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450000, China
| | - Kang Xu
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China.
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22
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Hanieh H, Bani Ismail M, Alfwuaires MA, Ibrahim HIM, Farhan M. Aryl Hydrocarbon Receptor as an Anticancer Target: An Overview of Ten Years Odyssey. Molecules 2023; 28:molecules28103978. [PMID: 37241719 DOI: 10.3390/molecules28103978] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/22/2023] [Accepted: 05/06/2023] [Indexed: 05/28/2023] Open
Abstract
Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor belonging to the basic helix-loop-helix (bHLH)/per-Arnt-sim (PAS) superfamily, is traditionally known to mediate xenobiotic metabolism. It is activated by structurally diverse agonistic ligands and regulates complicated transcriptional processes through its canonical and non-canonical pathways in normal and malignant cells. Different classes of AhR ligands have been evaluated as anticancer agents in different cancer cells and exhibit efficiency, which has thrust AhR into the limelight as a promising molecular target. There is strong evidence demonstrating the anticancer potential of exogenous AhR agonists including synthetic, pharmaceutical, and natural compounds. In contrast, several reports have indicated inhibition of AhR activity by antagonistic ligands as a potential therapeutic strategy. Interestingly, similar AhR ligands exert variable anticancer or cancer-promoting potential in a cell- and tissue-specific mode of action. Recently, ligand-mediated modulation of AhR signaling pathways and the associated tumor microenvironment is emerging as a potential approach for developing cancer immunotherapeutic drugs. This article reviews advances of AhR in cancer research covering publication from 2012 to early 2023. It summarizes the therapeutic potential of various AhR ligands with an emphasis on exogenous ligands. It also sheds light on recent immunotherapeutic strategies involving AhR.
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Affiliation(s)
- Hamza Hanieh
- Basic Medical Sciences Department, Faculty of Medicine, Aqaba Medical Sciences University, Aqaba 77110, Jordan
- International Medical Research Center (iMReC), Aqaba 77110, Jordan
| | - Mohammad Bani Ismail
- Basic Medical Sciences Department, Faculty of Medicine, Aqaba Medical Sciences University, Aqaba 77110, Jordan
| | - Manal A Alfwuaires
- Department of Biological Sciences, College of Science, King Faisal University, Hofuf 31982, Saudi Arabia
| | - Hairul-Islam M Ibrahim
- Department of Biological Sciences, College of Science, King Faisal University, Hofuf 31982, Saudi Arabia
| | - Mahdi Farhan
- International Medical Research Center (iMReC), Aqaba 77110, Jordan
- Department of Drug Development, UniTechPharma, 1700 Fribourg, Switzerland
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23
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Han JX, Tao ZH, Wang JL, Zhang L, Yu CY, Kang ZR, Xie Y, Li J, Lu S, Cui Y, Xu J, Zhao E, Wang M, Chen J, Wang Z, Liu Q, Chen HM, Su W, Zou TH, Zhou CB, Hong J, Chen H, Xiong H, Chen YX, Fang JY. Microbiota-derived tryptophan catabolites mediate the chemopreventive effects of statins on colorectal cancer. Nat Microbiol 2023; 8:919-933. [PMID: 37069401 DOI: 10.1038/s41564-023-01363-5] [Citation(s) in RCA: 83] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 03/16/2023] [Indexed: 04/19/2023]
Abstract
Epidemiological studies have indicated an association between statin use and reduced incidence of colorectal cancer (CRC), and work in preclinical models has demonstrated a potential chemopreventive effect. Statins are also associated with reduced dysbiosis in the gut microbiome, yet the role of the gut microbiome in the protective effect of statins in CRC is unclear. Here we validated the chemopreventive role of statins by retrospectively analysing a cohort of patients who underwent colonoscopies. This was confirmed in preclinical models and patient cohorts, and we found that reduced tumour burden was partly due to statin modulation of the gut microbiota. Specifically, the gut commensal Lactobacillus reuteri was increased as a result of increased microbial tryptophan availability in the gut after atorvastatin treatment. Our in vivo studies further revealed that L. reuteri administration suppressed colorectal tumorigenesis via the tryptophan catabolite, indole-3-lactic acid (ILA). ILA exerted anti-tumorigenic effects by downregulating the IL-17 signalling pathway. This microbial metabolite inhibited T helper 17 cell differentiation by targeting the nuclear receptor, RAR-related orphan receptor γt (RORγt). Together, our study provides insights into an anti-cancer mechanism driven by statin use and suggests that interventions with L. reuteri or ILA could complement chemoprevention strategies for CRC.
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Affiliation(s)
- Ji-Xuan Han
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhi-Hang Tao
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ji-Lin Wang
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lu Zhang
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chen-Yang Yu
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zi-Ran Kang
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuanhong Xie
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jialu Li
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shiyuan Lu
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yun Cui
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jia Xu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Enhao Zhao
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ming Wang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jinxian Chen
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zheng Wang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Liu
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hui-Min Chen
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wenyu Su
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Tian-Hui Zou
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Cheng-Bei Zhou
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Hong
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Haoyan Chen
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hua Xiong
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Ying-Xuan Chen
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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24
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Elson DJ, Kolluri SK. Tumor-Suppressive Functions of the Aryl Hydrocarbon Receptor (AhR) and AhR as a Therapeutic Target in Cancer. BIOLOGY 2023; 12:526. [PMID: 37106727 PMCID: PMC10135996 DOI: 10.3390/biology12040526] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/25/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023]
Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in regulating a wide range of biological responses. A diverse array of xenobiotics and endogenous small molecules bind to the receptor and drive unique phenotypic responses. Due in part to its role in mediating toxic responses to environmental pollutants, AhR activation has not been traditionally viewed as a viable therapeutic approach. Nonetheless, the expression and activation of AhR can inhibit the proliferation, migration, and survival of cancer cells, and many clinically approved drugs transcriptionally activate AhR. Identification of novel select modulators of AhR-regulated transcription that promote tumor suppression is an active area of investigation. The development of AhR-targeted anticancer agents requires a thorough understanding of the molecular mechanisms driving tumor suppression. Here, we summarized the tumor-suppressive mechanisms regulated by AhR with an emphasis on the endogenous functions of the receptor in opposing carcinogenesis. In multiple different cancer models, the deletion of AhR promotes increased tumorigenesis, but a precise understanding of the molecular cues and the genetic targets of AhR involved in this process is lacking. The intent of this review was to synthesize the evidence supporting AhR-dependent tumor suppression and distill insights for development of AhR-targeted cancer therapeutics.
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Affiliation(s)
- Daniel J. Elson
- Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA
| | - Siva K. Kolluri
- Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA
- Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
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25
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Niekamp P, Kim CH. Microbial Metabolite Dysbiosis and Colorectal Cancer. Gut Liver 2023; 17:190-203. [PMID: 36632785 PMCID: PMC10018301 DOI: 10.5009/gnl220260] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/09/2022] [Accepted: 08/18/2022] [Indexed: 01/13/2023] Open
Abstract
The global burden of colorectal cancer (CRC) is expected to continuously increase. Through research performed in the past decades, the effects of various environmental factors on CRC development have been well identified. Diet, the gut microbiota and their metabolites are key environmental factors that profoundly affect CRC development. Major microbial metabolites with a relevance for CRC prevention and pathogenesis include dietary fiber-derived short-chain fatty acids, bile acid derivatives, indole metabolites, polyamines, trimethylamine-N-oxide, formate, and hydrogen sulfide. These metabolites regulate various cell types in the intestine, leading to an altered intestinal barrier, immunity, chronic inflammation, and tumorigenesis. The physical, chemical, and metabolic properties of these metabolites along with their distinct functions to trigger host receptors appear to largely determine their effects in regulating CRC development. In this review, we will discuss the current advances in our understanding of the major CRC-regulating microbial metabolites, focusing on their production and interactive effects on immune responses and tumorigenesis in the colon.
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Affiliation(s)
- Patrick Niekamp
- Department of Pathology and Mary H. Weiser Food Allergy Center, Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Chang H. Kim
- Department of Pathology and Mary H. Weiser Food Allergy Center, Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
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26
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Safe S, Han H, Jayaraman A, Davidson LA, Allred CD, Ivanov I, Yang Y, Cai JJ, Chapkin RS. Aryl Hydrocarbon Receptor (AhR) Signaling in Colonic Cells and Tumors. RECEPTORS (BASEL, SWITZERLAND) 2023; 2:93-99. [PMID: 38651159 PMCID: PMC11034912 DOI: 10.3390/receptors2010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/25/2024]
Abstract
The aryl hydrocarbon receptor (AhR) is overexpressed in many tumor types and exhibits tumor-specific tumor promoter and tumor suppressor-like activity. In colon cancer, most but not all studies suggest that the AhR exhibits tumor suppressor activity which is enhanced by AhR ligands acting as agonists. Our studies investigated the role of the AhR in colon tumorigenesis using wild-type and AhR-knockout mice, the inflammation model of colon tumorigenesis using mice treated with azoxymethane (AOM)/dextran sodium sulfate (DSS) and APCS580/+; KrasG12D/+ mice all of which form intestinal tumors. The effects of tissue-specific AhR loss in the intestine of the tumor-forming mice on colonic stem cells, organoid-initiating capacity, colon tumor formation and mechanisms of AhR-mediated effects were investigated. Loss of AhR enhanced stem cell and tumor growth and in the AOM/DSS model AhR-dependent suppression of FOXM1 and downstream genes was important for AhR-dependent anticancer activity. Furthermore, the effectiveness of interleukin-22 (IL22) in colonic epithelial cells was also dependent on AhR expression. IL22 induced phosphorylation of STAT3, inhibited colonic organoid growth, promoted colonic cell proliferation in vivo and enhanced DNA repair in AOM/DSS-induced tumors. In this mouse model, the AhR suppressed SOCS3 expression and enhanced IL22-mediated activation of STAT3, whereas the loss of the AhR increased levels of SOCS3 which in turn inhibited IL22-induced STAT3 activation. In the APCS580/+; KrasG12D/+ mouse model, the loss of the AhR enhanced Wnt signaling and colon carcinogenesis. Results in both mouse models of colon carcinogenesis were complemented by single cell transcriptomics on colonic intestinal crypts which also showed that AhR deletion promoted expression of FOXM1-regulated genes in multiple colonic cell subtypes. These results support the role of the AhR as a tumor suppressor-like gene in the colon.
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Affiliation(s)
- Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA
| | - Huajun Han
- Program in Integrative Nutrition and Complex Diseases, Department of Nutrition, Texas A&M University, College Station, TX 77843, USA
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Laurie A. Davidson
- Program in Integrative Nutrition and Complex Diseases, Department of Nutrition, Texas A&M University, College Station, TX 77843, USA
| | - Clinton D. Allred
- Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC 27412, USA
| | - Ivan Ivanov
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA
| | - Yongjian Yang
- Program in Integrative Nutrition and Complex Diseases, Department of Nutrition, Texas A&M University, College Station, TX 77843, USA
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA
| | - James J. Cai
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA
| | - Robert S. Chapkin
- Program in Integrative Nutrition and Complex Diseases, Department of Nutrition, Texas A&M University, College Station, TX 77843, USA
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27
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Huang Q, Liu M, Zhang D, Lin BB, Fu X, Zhang Z, Zhang B, Dong JT. Nitazoxanide inhibits acetylated KLF5-induced bone metastasis by modulating KLF5 function in prostate cancer. BMC Med 2023; 21:68. [PMID: 36810084 PMCID: PMC9945734 DOI: 10.1186/s12916-023-02763-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 01/30/2023] [Indexed: 02/23/2023] Open
Abstract
BACKGROUND Castration-resistant prostate cancer often metastasizes to the bone, and such bone metastases eventually become resistant to available therapies, leading to the death of patients. Enriched in the bone, TGF-β plays a pivotal role in bone metastasis development. However, directly targeting TGF-β or its receptors has been challenging for the treatment of bone metastasis. We previously found that TGF-β induces and then depends on the acetylation of transcription factor KLF5 at K369 to regulate multiple biological processes, including the induction of EMT, cellular invasiveness, and bone metastasis. Acetylated KLF5 (Ac-KLF5) and its downstream effectors are thus potential therapeutic targets for treating TGF-β-induced bone metastasis in prostate cancer. METHODS A spheroid invasion assay was applied to prostate cancer cells expressing KLF5K369Q, which mimics Ac-KLF5, to screen 1987 FDA-approved drugs for invasion suppression. Luciferase- and KLF5K369Q-expressing cells were injected into nude mice via the tail artery to model bone metastasis. Bioluminescence imaging, micro-CT), and histological analyses were applied to monitor and evaluate bone metastases. RNA-sequencing, bioinformatic, and biochemical analyses were used to understand nitazoxanide (NTZ)-regulated genes, signaling pathways, and the underlying mechanisms. The binding of NTZ to KLF5 proteins was evaluated using fluorescence titration, high-performance liquid chromatography (HPLC), and circular dichroism (CD) analysis. RESULTS NTZ, an anthelmintic agent, was identified as a potent invasion inhibitor in the screening and validation assays. In KLF5K369Q-induced bone metastasis, NTZ exerted a potent inhibitory effect in preventive and therapeutic modes. NTZ also inhibited osteoclast differentiation, a cellular process responsible for bone metastasis induced by KLF5K369Q. NTZ attenuated the function of KLF5K369Q in 127 genes' upregulation and 114 genes' downregulation. Some genes' expression changes were significantly associated with worse overall survival in patients with prostate cancer. One such change was the upregulation of MYBL2, which functionally promotes bone metastasis in prostate cancer. Additional analyses demonstrated that NTZ bound to the KLF5 protein, KLF5K369Q bound to the promoter of MYBL2 to activate its transcription, and NTZ attenuated the binding of KLF5K369Q to the MYBL2 promoter. CONCLUSIONS NTZ is a potential therapeutic agent for bone metastasis induced by the TGF-β/Ac-KLF5 signaling axis in prostate cancer and likely other cancers.
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Affiliation(s)
- Qingqing Huang
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, 1088 Xueyuan Blvd, Shenzhen, 518055, China
| | - Mingcheng Liu
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, 1088 Xueyuan Blvd, Shenzhen, 518055, China
| | - Duo Zhang
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, 1088 Xueyuan Blvd, Shenzhen, 518055, China
| | - Bing-Biao Lin
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, 1088 Xueyuan Blvd, Shenzhen, 518055, China.,Department of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518000, China
| | - Xing Fu
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, 1088 Xueyuan Blvd, Shenzhen, 518055, China
| | - Zhiqian Zhang
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, 1088 Xueyuan Blvd, Shenzhen, 518055, China
| | - Baotong Zhang
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, 1088 Xueyuan Blvd, Shenzhen, 518055, China
| | - Jin-Tang Dong
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, 1088 Xueyuan Blvd, Shenzhen, 518055, China.
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Walcheck MT, Schwartz PB, Carrillo ND, Matkowsky KA, Nukaya M, Bradfield CA, Ronnekleiv-Kelly SM. Aryl hydrocarbon receptor knockout accelerates PanIN formation and fibro-inflammation in a mutant Kras-driven pancreatic cancer model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.01.526625. [PMID: 36778364 PMCID: PMC9915668 DOI: 10.1101/2023.02.01.526625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Objectives The pathogenesis of pancreas cancer (PDAC) remains poorly understood, hindering efforts to develop a more effective therapy for PDAC. Recent discoveries show the aryl hydrocarbon receptor (AHR) plays a crucial role in the pathogenesis of several cancers, and can be targeted for therapeutic effect. However, its involvement in PDAC remains unclear. Therefore, we evaluated the role of AHR in the development of PDAC in vivo. Methods We created a global AHR-null, mutant Kras-driven PDAC mouse model (A-/-KC) and evaluated the changes in PDAC precursor lesion formation (Pan-IN 1, 2, and 3) and associated fibro-inflammation between KC and A-/-KC at 5 months of age. We then examined the changes in the immune microenvironment followed by single-cell RNA-sequencing analysis to evaluate concomitant transcriptomic changes. Results We found a significant increase in PanIN-1 lesion formation and PanIN-1 associated fibro-inflammatory infiltrate in A-/-KC vs KC mice. This was associated with significant changes in the adaptive immune system, particularly a decrease in the CD4+/CD8+ T-cell ratio, as well as a decrease in the T-regulatory/Th17 T-cell ratio suggesting unregulated inflammation. Conclusion These findings show the loss of AHR results in heightened Kras-induced PanIN formation, through modulation of immune cells within the pancreatic tumor microenvironment.
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Affiliation(s)
- Morgan T Walcheck
- University of Wisconsin School of Medicine and Public Health, Department of Surgery, Division of Surgical Oncology, K4/747 CSC, 600 Highland Avenue, Madison, WI 53792
| | - Patrick B Schwartz
- University of Wisconsin School of Medicine and Public Health, Department of Surgery, Division of Surgical Oncology, K4/747 CSC, 600 Highland Avenue, Madison, WI 53792
| | - Noah D Carrillo
- University of Wisconsin, McArdle Laboratory for Cancer Research, 1400 University Avenue, McArdle Research Building, Madison, WI, 53706
| | - Kristina A Matkowsky
- University of Wisconsin School of Medicine and Public Health, Department of Pathology and Laboratory Medicine, L5/183 CSC, 600 Highland Avenue, Madison, WI 53792
- University of Wisconsin Carbone Cancer Center, Madison, WI 53705
- William S. Middleton Memorial Veterans Hospital, Madison, WI 53705
| | - Manabu Nukaya
- University of Wisconsin School of Medicine and Public Health, Department of Surgery, Division of Surgical Oncology, K4/747 CSC, 600 Highland Avenue, Madison, WI 53792
- University of Wisconsin, McArdle Laboratory for Cancer Research, 1400 University Avenue, McArdle Research Building, Madison, WI, 53706
| | - Christopher A Bradfield
- University of Wisconsin, McArdle Laboratory for Cancer Research, 1400 University Avenue, McArdle Research Building, Madison, WI, 53706
| | - Sean M Ronnekleiv-Kelly
- University of Wisconsin School of Medicine and Public Health, Department of Surgery, Division of Surgical Oncology, K4/747 CSC, 600 Highland Avenue, Madison, WI 53792
- University of Wisconsin, McArdle Laboratory for Cancer Research, 1400 University Avenue, McArdle Research Building, Madison, WI, 53706
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Safe S, Kothari J, Hailemariam A, Upadhyay S, Davidson LA, Chapkin RS. Health Benefits of Coffee Consumption for Cancer and Other Diseases and Mechanisms of Action. Int J Mol Sci 2023; 24:2706. [PMID: 36769029 PMCID: PMC9916720 DOI: 10.3390/ijms24032706] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/24/2023] [Accepted: 01/26/2023] [Indexed: 02/04/2023] Open
Abstract
Coffee is one of the most widely consumed beverages worldwide, and epidemiology studies associate higher coffee consumption with decreased rates of mortality and decreased rates of neurological and metabolic diseases, including Parkinson's disease and type 2 diabetes. In addition, there is also evidence that higher coffee consumption is associated with lower rates of colon and rectal cancer, as well as breast, endometrial, and other cancers, although for some of these cancers, the results are conflicting. These studies reflect the chemopreventive effects of coffee; there is also evidence that coffee consumption may be therapeutic for some forms of breast and colon cancer, and this needs to be further investigated. The mechanisms associated with the chemopreventive or chemotherapeutic effects of over 1000 individual compounds in roasted coffee are complex and may vary with different diseases. Some of these mechanisms may be related to nuclear factor erythroid 2 (Nrf2)-regulated pathways that target oxidative stress or pathways that induce reactive oxygen species to kill diseased cells (primarily therapeutic). There is evidence for the involvement of receptors which include the aryl hydrocarbon receptor (AhR) and orphan nuclear receptor 4A1 (NR4A1), as well as contributions from epigenetic pathways and the gut microbiome. Further elucidation of the mechanisms will facilitate the potential future clinical applications of coffee extracts for treating cancer and other inflammatory diseases.
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Affiliation(s)
- Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA
| | - Jainish Kothari
- Master of Biotechnology Program, Texas A&M University, College Station, TX 77843, USA
| | - Amanuel Hailemariam
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA
| | - Srijana Upadhyay
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA
| | - Laurie A. Davidson
- Program in Integrative Nutrition and Complex Diseases, Department of Nutrition, Texas A&M University, College Station, TX 77843, USA
| | - Robert S. Chapkin
- Program in Integrative Nutrition and Complex Diseases, Department of Nutrition, Texas A&M University, College Station, TX 77843, USA
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Vafaei S, Taheri H, Hajimomeni Y, Fakhre Yaseri A, Abolhasani Zadeh F. The role of NLRP3 inflammasome in colorectal cancer: potential therapeutic target. Clin Transl Oncol 2022; 24:1881-1889. [PMID: 35689136 DOI: 10.1007/s12094-022-02861-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 05/12/2022] [Indexed: 12/24/2022]
Abstract
All phases of carcinogenesis are affected by inflammation. Activation of the inflammasome is a crucial signaling mechanism that leads to acute and chronic inflammation. When specific nucleotide-binding domains, leucine-rich repeat-containing proteins (NLRs) are activated, inflammasomes are formed. The NLRP3 is one of the NLR family members with the most functional characterization. NLRP3 can modulate the immune systems, apoptosis, growth, and/or the gut microbiome to impact cancer development. Colorectal cancer (CRC) is one of the most common cancers, and it begins as a tissue overgrowth on the internal part of the rectum or colon. In vivo and in vitro studies showed that the NLRP3 inflammasome has a role in CRC development due to its broad activity in shaping immune responses. Here, onwards, we focus on the NLRP3 inflammasome role in CRC development, as well as the therapeutic prospective of modifying NLRP3 inflammasome in the context of anti-cancer therapy.
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Affiliation(s)
- Somayeh Vafaei
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Taheri
- Internal Medicine Cellular and Molecular, Research Center, Zahedan University of Medical Sciences, Fellowship of GI in Mashhad University of Medical Sciences, Zahedan, Iran
| | - Yasamin Hajimomeni
- Islamic Azad University of Medical Science, Qeshm International Branch, Qeshm, Iran
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Inhibition of Aryl Hydrocarbon Receptor (AhR) Expression Disrupts Cell Proliferation and Alters Energy Metabolism and Fatty Acid Synthesis in Colon Cancer Cells. Cancers (Basel) 2022; 14:cancers14174245. [PMID: 36077780 PMCID: PMC9454859 DOI: 10.3390/cancers14174245] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/12/2022] [Accepted: 08/25/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Cancer cells undergo metabolic modifications in order to meet their high energetic demand. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcriptional factor primarily known as a xenobiotic sensor. However, this receptor seems to have a wide range of physiological roles in many processes including cell proliferation, migration or control of immune responses. AhR is often overexpressed in tumor cells of various tissue origin, and several studies have indicated that AhR may also contribute to regulation of cellular metabolism, including synthesis of fatty acids (FA), one of the major steps in metabolic transition. Potential links between the AhR and the control of tumor cell proliferation and metabolism thus deserve more attention. Abstract The aryl hydrocarbon receptor (AhR) plays a wide range of physiological roles in cellular processes such as proliferation, migration or control of immune responses. Several studies have also indicated that AhR might contribute to the regulation of energy balance or cellular metabolism. We observed that the AhR is upregulated in tumor epithelial cells derived from colon cancer patients. Using wild-type and the corresponding AhR knockout (AhR KO) variants of human colon cancer cell lines HCT116 and HT-29, we analyzed possible role(s) of the AhR in cell proliferation and metabolism, with a focus on regulation of the synthesis of fatty acids (FAs). We observed a decreased proliferation rate in the AhR KO cells, which was accompanied with altered cell cycle progression, as well as a decreased ATP production. We also found reduced mRNA levels of key enzymes of the FA biosynthetic pathway in AhR KO colon cancer cells, in particular of stearoyl-CoA desaturase 1 (SCD1). The loss of AhR was also associated with reduced expression and/or activity of components of the PI3K/Akt pathway, which controls lipid metabolism, and other lipogenic transcriptional regulators, such as sterol regulatory element binding transcription factor 1 (SREBP1). Together, our data indicate that disruption of AhR activity in colon tumor cells may, likely in a cell-specific manner, limit their proliferation, which could be linked with a suppressive effect on their endogenous FA metabolism. More attention should be paid to potential mechanistic links between overexpressed AhR and colon tumor cell metabolism.
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Therachiyil L, Krishnankutty R, Ahmad F, Mateo JM, Uddin S, Korashy HM. Aryl Hydrocarbon Receptor Promotes Cell Growth, Stemness Like Characteristics, and Metastasis in Human Ovarian Cancer via Activation of PI3K/Akt, β-Catenin, and Epithelial to Mesenchymal Transition Pathways. Int J Mol Sci 2022; 23:6395. [PMID: 35742838 PMCID: PMC9223661 DOI: 10.3390/ijms23126395] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 12/15/2022] Open
Abstract
Ovarian cancer (OC) ranks first in cancer-related deaths out of all female reproductive malignancies with high-pitched tumor relapse and chemoresistance. Several reports correlate cancer occurrences with exposure to xenobiotics via induction of a protein receptor named aryl hydrocarbon receptor (AhR). However, the effect of AhR on OC proliferation, expansion, and chemoresistance remains unrevealed. For this purpose, OC cells A2780 and A2780cis cells were treated with AhR activator, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and the effects were determined by Real-Time Cell Analyzer, clonogenic assay, flow cytometry, immunoblotting and wound healing assay. Our results showed that activation of AhR by TCDD in A2780 cells induced the PI3K/AKT pathway followed by induction of anti-apoptotic proteins BCL-2, BCL-xl, and MCL-1. In addition, a significant increase in stemness marker aldehyde dehydrogenase (ALDH1) was observed. This effect was also associated with an accumulation of β-catenin, a Wnt transcription factor. Moreover, we observed induction of epithelial to mesenchymal transition (EMT) upon AhR activation. In conclusion, the results from the current study confirm that AhR mediates OC progression, stemness characteristics, and metastatic potential via activation of PI3K/Akt, Wnt/β-catenin, and EMT. This study provides a better insight into the modulatory role of AhR that might help in developing novel therapeutic strategies for OC treatment.
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Affiliation(s)
- Lubna Therachiyil
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar;
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha P.O. Box 2713, Qatar; (R.K.); (F.A.); (J.M.M.); (S.U.)
| | - Roopesh Krishnankutty
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha P.O. Box 2713, Qatar; (R.K.); (F.A.); (J.M.M.); (S.U.)
| | - Fareed Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha P.O. Box 2713, Qatar; (R.K.); (F.A.); (J.M.M.); (S.U.)
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha P.O. Box 2713, Qatar
| | - Jericha M. Mateo
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha P.O. Box 2713, Qatar; (R.K.); (F.A.); (J.M.M.); (S.U.)
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha P.O. Box 2713, Qatar; (R.K.); (F.A.); (J.M.M.); (S.U.)
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha P.O. Box 2713, Qatar
| | - Hesham M. Korashy
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar;
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Vaghari-Tabari M, Targhazeh N, Moein S, Qujeq D, Alemi F, Majidina M, Younesi S, Asemi Z, Yousefi B. From inflammatory bowel disease to colorectal cancer: what's the role of miRNAs? Cancer Cell Int 2022; 22:146. [PMID: 35410210 PMCID: PMC8996392 DOI: 10.1186/s12935-022-02557-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 03/21/2022] [Indexed: 12/27/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease with relapse and remission periods. Ulcerative colitis and Crohn's disease are two major forms of the disease. IBD imposes a lot of sufferings on the patient and has many consequences; however, the most important is the increased risk of colorectal cancer, especially in patients with Ulcerative colitis. This risk is increased with increasing the duration of disease, thus preventing the progression of IBD to cancer is very important. Therefore, it is necessary to know the details of events contributed to the progression of IBD to cancer. In recent years, the importance of miRNAs as small molecules with 20-22 nucleotides has been recognized in pathophysiology of many diseases, in which IBD and colorectal cancer have not been excluded. As a result, the effectiveness of these small molecules as therapeutic target is hopefully confirmed. This paper has reviewed the related studies and findings about the role of miRNAs in the course of events that promote the progression of IBD to colorectal carcinoma, as well as a review about the effectiveness of some of these miRNAs as therapeutic targets.
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Affiliation(s)
- Mostafa Vaghari-Tabari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Targhazeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Moein
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Forough Alemi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidina
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Simin Younesi
- Schoole of Health and Biomedical Sciences, RMIT University, Melborne, VIC, Australia
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Cancer immunotherapy resistance: The impact of microbiome-derived short-chain fatty acids and other emerging metabolites. Life Sci 2022; 300:120573. [DOI: 10.1016/j.lfs.2022.120573] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 04/10/2022] [Accepted: 04/18/2022] [Indexed: 12/12/2022]
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Ma L, Yu J, Zhang H, Zhao B, Zhang J, Yang D, Luo F, Wang B, Jin B, Liu J. Effects of Immune Cells on Intestinal Stem Cells: Prospects for Therapeutic Targets. Stem Cell Rev Rep 2022; 18:2296-2314. [DOI: 10.1007/s12015-022-10347-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/27/2022] [Indexed: 11/29/2022]
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Li J, Zhang AH, Wu FF, Wang XJ. Alterations in the Gut Microbiota and Their Metabolites in Colorectal Cancer: Recent Progress and Future Prospects. Front Oncol 2022; 12:841552. [PMID: 35223525 PMCID: PMC8875205 DOI: 10.3389/fonc.2022.841552] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/18/2022] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality worldwide. The etiology and pathogenesis of CRC remain unclear. A growing body of evidence suggests dysbiosis of gut bacteria can contribute to the occurrence and development of CRC by generating harmful metabolites and changing host physiological processes. Metabolomics, a systems biology method, will systematically study the changes in metabolites in the physiological processes of the body, eventually playing a significant role in the detection of metabolic biomarkers and improving disease diagnosis and treatment. Metabolomics, in particular, has been highly beneficial in tracking microbially derived metabolites, which has substantially advanced our comprehension of host-microbiota metabolic interactions in CRC. This paper has briefly compiled recent research progress of the alterations of intestinal flora and its metabolites associated with CRC and the application of association analysis of metabolomics and gut microbiome in the diagnosis, prevention, and treatment of CRC; furthermore, we discuss the prospects for the problems and development direction of this association analysis in the study of CRC. Gut microbiota and their metabolites influence the progression and causation of CRC, and the association analysis of metabolomics and gut microbiome will provide novel strategies for the prevention, diagnosis, and therapy of CRC.
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Affiliation(s)
- Jing Li
- National Engineering Laboratory for the Development of Southwestern Endangered Medicinal Materials, Guangxi Botanical Garden of Medicinal Plant, Nanning, China
- National Chinmedomics Research Center, National Traditional Chinese Medicine (TCM) Key Laboratory of Serum Pharmacochemistry, Functional Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Ai-hua Zhang
- National Chinmedomics Research Center, National Traditional Chinese Medicine (TCM) Key Laboratory of Serum Pharmacochemistry, Functional Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Fang-fang Wu
- National Engineering Laboratory for the Development of Southwestern Endangered Medicinal Materials, Guangxi Botanical Garden of Medicinal Plant, Nanning, China
| | - Xi-jun Wang
- National Engineering Laboratory for the Development of Southwestern Endangered Medicinal Materials, Guangxi Botanical Garden of Medicinal Plant, Nanning, China
- National Chinmedomics Research Center, National Traditional Chinese Medicine (TCM) Key Laboratory of Serum Pharmacochemistry, Functional Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Harbin, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
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Yang Y, Osorio D, Davidson LA, Han H, Mullens DA, Jayaraman A, Safe S, Ivanov I, Cai JJ, Chapkin RS. Single-cell RNA Sequencing Reveals How the Aryl Hydrocarbon Receptor Shapes Cellular Differentiation Potency in the Mouse Colon. Cancer Prev Res (Phila) 2022; 15:17-28. [PMID: 34815312 PMCID: PMC8741728 DOI: 10.1158/1940-6207.capr-21-0378] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/18/2021] [Accepted: 11/16/2021] [Indexed: 11/16/2022]
Abstract
Despite recent progress recognizing the importance of aryl hydrocarbon receptor (Ahr)-dependent signaling in suppressing colon tumorigenesis, its role in regulating colonic crypt homeostasis remains unclear. To assess the effects of Ahr on intestinal epithelial cell heterogeneity and functional phenotypes, we utilized single-cell transcriptomics and advanced analytic strategies to generate a high-quality atlas for colonic intestinal crypts from wild-type and intestinal-specific Ahr knockout mice. Here we observed the promotive effects of Ahr deletion on Foxm1-regulated genes in crypt-associated canonical epithelial cell types and subtypes of goblet cells and deep crypt-secretory cells. We also show that intestinal Ahr deletion elevated single-cell entropy (a measure of differentiation potency or cell stemness) and RNA velocity length (a measure of the rate of cell differentiation) in noncycling and cycling Lgr5+ stem cells. In general, intercellular signaling cross-talk via soluble and membrane-bound factors was perturbed in Ahr-null colonocytes. Taken together, our single-cell RNA sequencing analyses provide new evidence of the molecular function of Ahr in modulating putative stem cell driver genes, cell potency lineage decisions, and cell-cell communication in vivo. PREVENTION RELEVANCE: Our mouse single-cell RNA sequencing analyses provide new evidence of the molecular function of Ahr in modulating colonic stemness and cell-cell communication in vivo. From a cancer prevention perspective, Ahr should be considered a therapeutic target to recalibrate remodeling of the intestinal stem cell niche.
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Affiliation(s)
- Yongjian Yang
- Department of Electrical & Computer Engineering, Texas A&M University, College Station, Texas
| | - Daniel Osorio
- Department of Veterinary Integrative Biosciences, Texas A&M University College of Veterinary Medicine and Biomedical Sciences, College Station, Texas
| | - Laurie A Davidson
- Department of Nutrition, Texas A&M University, College Station, Texas
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas
| | - Huajun Han
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas
| | - Destiny A Mullens
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas
- Department of Veterinary Pathobiology, Texas A&M University College of Veterinary Medicine and Biomedical Sciences, College Station, Texas
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, College Station, Texas
| | - Stephen Safe
- Department of Veterinary Physiology & Pharmacology, Texas A&M University College of Veterinary Medicine and Biomedical Sciences, College Station, Texas
| | - Ivan Ivanov
- Department of Veterinary Pathobiology, Texas A&M University College of Veterinary Medicine and Biomedical Sciences, College Station, Texas
| | - James J Cai
- Department of Electrical & Computer Engineering, Texas A&M University, College Station, Texas
- Department of Veterinary Integrative Biosciences, Texas A&M University College of Veterinary Medicine and Biomedical Sciences, College Station, Texas
| | - Robert S Chapkin
- Department of Nutrition, Texas A&M University, College Station, Texas.
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas
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Han H, Davidson LA, Fan YY, Landrock KK, Jayaraman A, Safe SH, Chapkin RS. Loss of aryl hydrocarbon receptor suppresses the response of colonic epithelial cells to IL22 signaling by upregulating SOCS3. Am J Physiol Gastrointest Liver Physiol 2022; 322:G93-G106. [PMID: 34755534 PMCID: PMC8714253 DOI: 10.1152/ajpgi.00074.2021] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 11/04/2021] [Accepted: 11/08/2021] [Indexed: 01/31/2023]
Abstract
IL22 signaling plays an important role in maintaining gastrointestinal epithelial barrier function, cell proliferation, and protection of intestinal stem cells from genotoxicants. Emerging studies indicate that the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, promotes production of IL22 in gut immune cells. However, it remains to be determined if AhR signaling can also affect the responsiveness of colonic epithelial cells to IL22. Here, we show that IL22 treatment induces the phosphorylation of STAT3, inhibits colonic organoid growth, and promotes colonic cell proliferation in vivo. Notably, intestinal cell-specific AhR knockout (KO) reduces responsiveness to IL22 and compromises DNA damage response after exposure to carcinogen, in part due to the enhancement of suppressor of cytokine signaling 3 (SOCS3) expression. Deletion of SOCS3 increases levels of pSTAT3 in AhR KO organoids, and phenocopies the effects of IL22 treatment on wild-type (WT) organoid growth. In addition, pSTAT3 levels are inversely associated with increased azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon tumorigenesis in AhR KO mice. These findings indicate that AhR function is required for optimal IL22 signaling in colonic epithelial cells and provide rationale for targeting AhR as a means of reducing colon cancer risk.NEW & NOTEWORTHY AhR is a key transcription factor controlling expression of IL22 in gut immune cells. In this study, we show for the first time that AhR signaling also regulates IL22 response in colonic epithelial cells by modulating SOCS3 expression.
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Affiliation(s)
- Huajun Han
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas
| | - Laurie A Davidson
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Yang-Yi Fan
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Kerstin K Landrock
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, College Station, Texas
| | - Stephen H Safe
- Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Robert S Chapkin
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas
- Department of Nutrition, Texas A&M University, College Station, Texas
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Taddese R, Roelofs R, Draper D, Wu X, Wu S, Swinkels DW, Tjalsma H, Boleij A. Streptococcus gallolyticus Increases Expression and Activity of Aryl Hydrocarbon Receptor-Dependent CYP1 Biotransformation Capacity in Colorectal Epithelial Cells. Front Cell Infect Microbiol 2021; 11:740704. [PMID: 34778104 PMCID: PMC8579041 DOI: 10.3389/fcimb.2021.740704] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 10/04/2021] [Indexed: 12/16/2022] Open
Abstract
Objective The opportunistic pathogen Streptococcus gallolyticus is one of the few intestinal bacteria that has been consistently linked to colorectal cancer (CRC). This study aimed to identify novel S. gallolyticus-induced pathways in colon epithelial cells that could further explain how S. gallolyticus contributes to CRC development. Design and Results Transcription profiling of in vitro cultured CRC cells that were exposed to S. gallolyticus revealed the specific induction of oxidoreductase pathways. Most prominently, CYP1A and ALDH1 genes that encode phase I biotransformation enzymes were responsible for the detoxification or bio-activation of toxic compounds. A common feature is that these enzymes are induced through the Aryl hydrocarbon receptor (AhR). Using the specific inhibitor CH223191, we showed that the induction of CYP1A was dependent on the AhR both in vitro using multiple CRC cell lines as in vivo using wild-type C57bl6 mice colonized with S. gallolyticus. Furthermore, we showed that CYP1 could also be induced by other intestinal bacteria and that a yet unidentified diffusible factor from the S. galloltyicus secretome (SGS) induces CYP1A enzyme activity in an AhR-dependent manner. Importantly, priming CRC cells with SGS increased the DNA damaging effect of the polycyclic aromatic hydrocarbon 3-methylcholanthrene. Conclusion This study shows that gut bacteria have the potential to modulate the expression of biotransformation pathways in colonic epithelial cells in an AhR-dependent manner. This offers a novel theory on the contribution of intestinal bacteria to the etiology of CRC by modifying the capacity of intestinal epithelial or (pre-)cancerous cells to (de)toxify dietary components, which could alter intestinal susceptibility to DNA damaging events.
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Affiliation(s)
- Rahwa Taddese
- Department of Pathology, Nijmegen Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Centre (Radboudumc), Nijmegen, Netherlands
| | - Rian Roelofs
- Laboratory Medicine, Nijmegen Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Centre (Radboudumc), Nijmegen, Netherlands
| | - Derk Draper
- Department of Pathology, Nijmegen Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Centre (Radboudumc), Nijmegen, Netherlands
| | - Xinqun Wu
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins University, Baltimore, MD, United States
| | - Shaoguang Wu
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins University, Baltimore, MD, United States
| | - Dorine W Swinkels
- Laboratory Medicine, Nijmegen Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Centre (Radboudumc), Nijmegen, Netherlands
| | - Harold Tjalsma
- Laboratory Medicine, Nijmegen Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Centre (Radboudumc), Nijmegen, Netherlands
| | - Annemarie Boleij
- Department of Pathology, Nijmegen Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Centre (Radboudumc), Nijmegen, Netherlands
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Han H, Safe S, Jayaraman A, Chapkin RS. Diet-Host-Microbiota Interactions Shape Aryl Hydrocarbon Receptor Ligand Production to Modulate Intestinal Homeostasis. Annu Rev Nutr 2021; 41:455-478. [PMID: 34633858 PMCID: PMC8667662 DOI: 10.1146/annurev-nutr-043020-090050] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated basic-helix-loop-helix transcription factor that binds structurally diverse ligands and senses cues from environmental toxicants and physiologically relevant dietary/microbiota-derived ligands. The AhR is an ancient conserved protein and is widely expressed across different tissues in vertebrates and invertebrates. AhR signaling mediates a wide range of cellular functions in a ligand-, cell type-, species-, and context-specific manner. Dysregulation of AhR signaling is linked to many developmental defects and chronic diseases. In this review, we discuss the emerging role of AhR signaling in mediating bidirectional host-microbiome interactions. We also consider evidence showing the potential for the dietary/microbial enhancement ofhealth-promoting AhR ligands to improve clinical pathway management in the context of inflammatory bowel diseases and colon tumorigenesis.
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Affiliation(s)
- Huajun Han
- Program in Integrative Nutrition and Complex Diseases and Department of Nutrition, Texas A&M University, College Station, Texas 77843, USA;
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas 77843, USA
| | - Stephen Safe
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas 77843, USA
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843, USA
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, College Station, Texas 77843, USA
| | - Robert S Chapkin
- Program in Integrative Nutrition and Complex Diseases and Department of Nutrition, Texas A&M University, College Station, Texas 77843, USA;
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas 77843, USA
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41
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Chapkin RS, Davidson LA, Park H, Jin UH, Fan YY, Cheng Y, Hensel ME, Landrock KK, Allred C, Menon R, Klemashevich C, Jayaraman A, Safe S. Role of the Aryl Hydrocarbon Receptor (AhR) in Mediating the Effects of Coffee in the Colon. Mol Nutr Food Res 2021; 65:e2100539. [PMID: 34406707 PMCID: PMC8530922 DOI: 10.1002/mnfr.202100539] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/26/2021] [Indexed: 12/14/2022]
Abstract
SCOPE This study investigates the mechanism of action and functional effects of coffee extracts in colonic cells, on intestinal stem cell growth, and inhibition of dextran sodium sulfate (DSS)-induced intestinal barrier damage in mice. METHODS AND RESULTS Aqueous coffee extracts induced Ah receptor (AhR) -responsive CYP1A1, CYP1B1, and UGT1A1 gene expression in colon-derived Caco2 and YAMC cells. Tissue-specific AhR knockout (AhRf/f x Lgr5-GFP-CreERT2 x Villin-Cre), wild-type (Lgr5-CreERT2 x Villin-Cre) mice are sources of stem cell enriched organoids and both coffee extracts and norharman, an AhR-active component of these extracts inhibited stem cell growth. Coffee extracts also inhibit DSS-induced damage to intestinal barrier function and DSS-induced mucosal inflammatory genes such as IL-6 and TGF-β1 in wild-type (AhR+/+ ) but not AhR-/- mice. In contrast, coffee does not exhibit protective effects in intestinal-specific AhR knockout mice. Coffee extracts also enhanced overall formation of AhR-active microbial metabolites. CONCLUSIONS In colon-derived cells and in the mouse intestine, coffee induced several AhR-dependent responses including gene expression, inhibition of intestinal stem cell-enriched organoid growth, and inhibition of DSS-induced intestinal barrier damage. We conclude that the anti-inflammatory effects of coffee in the intestine are due, in part, to activation of AhR signaling.
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Affiliation(s)
- Robert S. Chapkin
- Departments of Nutrition and Biochemistry & Biophysics Texas A&M University, College Station, TX, USA, 77843
| | - Laurie A. Davidson
- Departments of Nutrition and Biochemistry & Biophysics Texas A&M University, College Station, TX, USA, 77843
| | - Hyejin Park
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA, 77843
| | - Un-Ho Jin
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA, 77843
| | - Yang-Yi Fan
- Departments of Nutrition and Biochemistry & Biophysics Texas A&M University, College Station, TX, USA, 77843
| | - Yating Cheng
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA, 77843
| | - Martha E. Hensel
- Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, USA, 77843
| | - Kerstin K. Landrock
- Departments of Nutrition and Biochemistry & Biophysics Texas A&M University, College Station, TX, USA, 77843
| | - Clinton Allred
- Departments of Nutrition and Biochemistry & Biophysics Texas A&M University, College Station, TX, USA, 77843
| | - Rani Menon
- Department of Chemical Engineering, Texas A&M University, College Station, TX, USA, 77843
| | - Cory Klemashevich
- Department of Chemical Engineering, Texas A&M University, College Station, TX, USA, 77843
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, College Station, TX, USA, 77843
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA, 77843
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42
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Bock KW. Aryl hydrocarbon receptor (AHR) functions in infectious and sterile inflammation and NAD +-dependent metabolic adaptation. Arch Toxicol 2021; 95:3449-3458. [PMID: 34559251 PMCID: PMC8461142 DOI: 10.1007/s00204-021-03134-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 08/11/2021] [Indexed: 01/13/2023]
Abstract
Aryl hydrocarbon receptor (AHR) research has shifted from exploring dioxin toxicity to elucidation of various physiologic AHR functions. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to exert cellular stress-mediated sterile inflammatory responses in exposed human tissues but may be lethal in sensitive species. Inflammation can be thought of as the extreme end of a spectrum ranging from homeostasis to stress responses (sterile inflammation) and to defense against infection (infectious inflammation). Defense against bacterial infection by generation of reactive oxygen species has to be strictly controlled and may use up a considerable amount of energy. NAD+-mediated energy metabolism adapts to various inflammatory responses. As examples, the present commentary tries to integrate responses of AHR and NAD+-consuming enzymes (PARP7/TiPARP, CD38 and sirtuins) into infectious and stress-induced inflammatory responses, the latter exemplified by nonalcoholic fatty liver disease (NAFLD). TCDD toxicity models in sensitive species provide hints to molecular AHR targets of energy metabolism including gluconeogenesis and glycolysis. AHR research remains challenging and promising.
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Affiliation(s)
- Karl Walter Bock
- Institute of Experimental and Clinical Pharmacology and Toxicology, Wilhelmstrasse 56, 72074, Tübingen, Germany.
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43
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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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44
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Wilson RH, Carney PR, Glover E, Parrott JC, Rojas BL, Moran SM, Yee JS, Nukaya M, Goetz NA, Rubinstein CD, Krentz KJ, Xing Y, Bradfield CA. Generation of an Allelic Series at the Ahr Locus Using an Edited Recombinant Approach. Toxicol Sci 2021; 180:239-251. [PMID: 33480436 DOI: 10.1093/toxsci/kfab005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and a member of the PER-ARNT-SIM (PAS) superfamily of environmental sensors. The AHR is involved in a series of biological processes including adaptive metabolism of xenobiotics, toxicity of certain environmental pollutants, vascular development, fertility, and immune function. Mouse models, including the Ahr null and Ahr conditional null (Ahrfx) mice, are widely used for the study of AHR-mediated biology and toxicity. The Ahr conditional null mouse harbors the low-affinity Ahrd allele that exhibits approximately a 10-fold lower binding affinity for certain xenobiotic AHR ligands than the widely used C57BL/6 mouse that harbors the higher affinity Ahrb1 allele. Here, we report a novel mouse model that introduces a V375A polymorphism that converts the low-affinity allele into a high-affinity allele, offering a more sensitive conditional model. In the generation of this novel conditional allele, two additional mutants arose, including a 3-bp deletion in the PAS-B domain (AhrNG367R) and an early termination codon in the PAS-B domain (AhrTer383). The AhrNG367R allele presents as a phenocopy of the null and the AhrTer383 allele presents as an antimorph when assessing for the ductus venosus and liver lobe weight endpoints. These new models represent a series of tools that will be useful in further characterizing AHR biology.
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Affiliation(s)
- Rachel H Wilson
- Molecular and Environmental Toxicology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.,Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
| | - Patrick R Carney
- Molecular and Environmental Toxicology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.,Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
| | - Edward Glover
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
| | - Jessica C Parrott
- Molecular and Environmental Toxicology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.,Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
| | - Brenda L Rojas
- Molecular and Environmental Toxicology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.,Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.,Biotechnology Center, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
| | - Susan M Moran
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
| | - Jeremiah S Yee
- Molecular and Environmental Toxicology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.,Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
| | - Manabu Nukaya
- Molecular and Environmental Toxicology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
| | - Nicholas A Goetz
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
| | - Clifford D Rubinstein
- Biotechnology Center, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
| | - Kathy J Krentz
- Biotechnology Center, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
| | - Yongna Xing
- Molecular and Environmental Toxicology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.,Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
| | - Christopher A Bradfield
- Molecular and Environmental Toxicology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.,Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.,Biotechnology Center, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
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45
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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: 211] [Impact Index Per Article: 52.8] [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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46
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Ala M. Tryptophan metabolites modulate inflammatory bowel disease and colorectal cancer by affecting immune system. Int Rev Immunol 2021; 41:326-345. [PMID: 34289794 DOI: 10.1080/08830185.2021.1954638] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Tryptophan is an essential amino acid, going through three different metabolic pathways in the intestines. Indole pathway in the gut microbiota, serotonin system in the enterochromaffin cells and kynurenine pathway in the immune cells and intestinal lining are the three arms of tryptophan metabolism in the intestines. Clinical, in vivo and in vitro studies showed that each one of these arms has a significant impact on IBD. This review explains how different metabolites of tryptophan are involved in the pathophysiology of IBD and colorectal cancer, as a major complication of IBD. Indole metabolites alleviate colitis and protect against colorectal cancer while serotonin arm follows a more complicated and receptor-specific pattern. Indole metabolites and kynurenine interact with aryl hydrocarbon receptor (AHR) to induce T regulatory cells differentiation, confine Th17 and Th1 response and produce anti-inflammatory mediators. Kynurenine decreases tumor-infiltrating CD8+ cells and mediates tumor cells immune evasion. Serotonin system also increases colorectal cancer cells proliferation and metastasis while, indole metabolites can profoundly decrease colorectal cancer growth. Targeted therapy for tryptophan metabolites may improve the management of IBD and colorectal cancer, e.g. supplementation of indole metabolites such as indole-3-carbinol (I3C), inhibition of kynurenine monooxygenase (KMO) and selective stimulation or inhibition of specific serotonergic receptors can mitigate colitis. Furthermore, it will be explained how indole metabolites supplementation, inhibition of indoleamine 2,3-dioxygenase 1 (IDO1), KMO and serotonin receptors can protect against colorectal cancer. Additionally, extensive molecular interactions between tryptophan metabolites and intracellular signaling pathways will be thoroughly discussed.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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47
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Han H, Davidson LA, Hensel M, Yoon G, Landrock K, Allred C, Jayaraman A, Ivanov I, Safe SH, Chapkin RS. Loss of Aryl Hydrocarbon Receptor Promotes Colon Tumorigenesis in ApcS580/+; KrasG12D/+ Mice. Mol Cancer Res 2021; 19:771-783. [PMID: 33495399 PMCID: PMC8137548 DOI: 10.1158/1541-7786.mcr-20-0789] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 12/03/2020] [Accepted: 01/14/2021] [Indexed: 11/16/2022]
Abstract
The mutational genetic landscape of colorectal cancer has been extensively characterized; however, the ability of "cooperation response genes" to modulate the function of cancer "driver" genes remains largely unknown. In this study, we investigate the role of aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, in modulating oncogenic cues in the colon. We show that intestinal epithelial cell-targeted AhR knockout (KO) promotes the expansion and clonogenic capacity of colonic stem/progenitor cells harboring ApcS580/+; KrasG12D/+ mutations by upregulating Wnt signaling. The loss of AhR in the gut epithelium increased cell proliferation, reduced mouse survival rate, and promoted cecum and colon tumorigenesis in mice. Mechanistically, the antagonism of Wnt signaling induced by Lgr5 haploinsufficiency attenuated the effects of AhR KO on cecum and colon tumorigenesis. IMPLICATIONS: Our findings reveal that AhR signaling plays a protective role in genetically induced colon tumorigenesis at least by suppressing Wnt signaling and provides rationale for the AhR as a therapeutic target for cancer prevention and treatment.
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Affiliation(s)
- Huajun Han
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas
| | - Laurie A Davidson
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Martha Hensel
- Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas
| | - Grace Yoon
- Department of Statistics, Texas A&M University, College Station, Texas
| | - Kerstin Landrock
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Clinton Allred
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, College Station, Texas
| | - Ivan Ivanov
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Stephen H Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Robert S Chapkin
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, Texas.
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas
- Department of Nutrition, Texas A&M University, College Station, Texas
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48
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Sun XZ, Zhao DY, Zhou YC, Wang QQ, Qin G, Yao SK. Alteration of fecal tryptophan metabolism correlates with shifted microbiota and may be involved in pathogenesis of colorectal cancer. World J Gastroenterol 2020; 26:7173-7190. [PMID: 33362375 PMCID: PMC7723673 DOI: 10.3748/wjg.v26.i45.7173] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 10/12/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gut tryptophan (Trp) metabolites are produced by microbiota and/or host metabolism. Some of them have been proven to promote or inhibit colorectal cancer (CRC) in vitro and animal models. We hypothesized that there is an alteration of gut Trp metabolism mediated by microbiota and that it might be involved in the pathogenesis of cancer in patients with CRC. AIM To investigate the features of Trp metabolism in CRC and the correlation between fecal Trp metabolites and gut microbiota. METHODS Seventy-nine patients with colorectal neoplastic lesions (33 with colon adenoma and 46 with sporadic CRC) and 38 healthy controls (HCs) meeting the inclusion and exclusion criteria were included in the study. Their demographic and clinical features were collected. Fecal Trp, kynurenine (KYN), and indoles (metabolites of Trp metabolized by gut microbiota) were examined by ultraperformance liquid chromatography coupled to tandem mass spectrometry. Gut barrier marker and indoleamine 2,3-dioxygenase 1 (IDO1) mRNA were analyzed by quantitative real-time polymerase chain reaction. Zonula occludens-1 (ZO-1) protein expression was analyzed by immunohistochemistry. The gut microbiota was detected by 16S ribosomal RNA gene sequencing. Correlations between fecal metabolites and other parameters were examined in all patients. RESULTS The absolute concentration of KYN [1.51 (0.70, 3.46) nmol/g vs 0.81 (0.64, 1.57) nmol/g, P = 0.036] and the ratio of KYN to Trp [7.39 (4.12, 11.72) × 10-3 vs 5.23 (1.86, 7.99) × 10-3, P = 0.032] were increased in the feces of patients with CRC compared to HCs, while the indoles to Trp ratio was decreased [1.34 (0.70, 2.63) vs 2.46 (1.25, 4.10), P = 0.029]. The relative ZO-1 mRNA levels in patients with CRC (0.27 ± 0.24) were significantly lower than those in HCs (1.00 ± 0.31) (P < 0.001), and the relative IDO1 mRNA levels in patients with CRC [1.65 (0.47-2.46)] were increased (P = 0.035). IDO1 mRNA levels were positively associated with the KYN/Trp ratio (r = 0.327, P = 0.003). ZO-1 mRNA and protein levels were positively correlated with the indoles/Trp ratio (P = 0.035 and P = 0.009, respectively). In addition, the genera Asaccharobacter (Actinobacteria) and Parabacteroides (Bacteroidetes), and members of the phylum Firmicutes (Clostridium XlVb, Fusicatenibacter, Anaerofilum, and Anaerostipes) decreased in CRC and exhibited a positive correlation with indoles in all subjects. CONCLUSION Alteration of fecal Trp metabolism mediated by microbiota is associated with intestinal barrier function and tissue Trp metabolism, and may be involved in the pathogenesis of CRC.
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Affiliation(s)
- Xi-Zhen Sun
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Dong-Yan Zhao
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yuan-Chen Zhou
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
- Peking University China-Japan Friendship School of Clinical Medicine, Peking University, Beijing 100029, China
| | - Qian-Qian Wang
- Peking University China-Japan Friendship School of Clinical Medicine, Peking University, Beijing 100029, China
| | - Geng Qin
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Shu-Kun Yao
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
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Han H, Jayaraman A, Safe S, Chapkin RS. Targeting the aryl hydrocarbon receptor in stem cells to improve the use of food as medicine. CURRENT STEM CELL REPORTS 2020; 6:109-118. [PMID: 34395177 PMCID: PMC8362759 DOI: 10.1007/s40778-020-00184-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/04/2020] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Intestinal stem cells, the most rapidly proliferating adult stem cells, are exquisitely sensitive to extrinsic dietary factors. Uncontrolled regulation of intestinal stem cells is closely linked to colon tumorigenesis. This review focuses on how dietary and microbial derived cues regulate intestinal stem cell functionality and colon tumorigenesis in mouse models by targeting the aryl hydrocarbon receptor (AhR). RECENT FINDINGS AhR, a ligand activated transcription factor, can integrate environmental, dietary and microbial cues to modulate intestinal stem cell proliferation, differentiation and their microenvironment, affecting colon cancer risk. Modulation of AhR activity is associated with many chronic diseases, including inflammatory bowel diseases where AhR expression is protective. SUMMARY AhR signaling controls the maintenance and differentiation of intestinal stem cells, influences local niche factors, and plays a protective role in colon tumorigenesis. Mounting evidence suggests that extrinsic nutritional/dietary cues which modulate AhR signaling may be a promising approach to colon cancer chemoprevention.
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Affiliation(s)
- Huajun Han
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, 77843
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX, 77843
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, College Station, TX, 77843
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, 77843
| | - Robert S. Chapkin
- Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, 77843
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX, 77843
- Department of Nutrition, Texas A&M University, College Station, TX, 77843
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Bock KW. Aryl hydrocarbon receptor (AHR), integrating energy metabolism and microbial or obesity-mediated inflammation. Biochem Pharmacol 2020; 184:114346. [PMID: 33227291 DOI: 10.1016/j.bcp.2020.114346] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 11/17/2020] [Accepted: 11/18/2020] [Indexed: 02/07/2023]
Abstract
Aryl hydrocarbon receptor (AHR) has been characterized as multifunctional sensor, integrator and ligand-activated transcription factor of the bHLH/PAS family. Regulation of inflammatory diseases and energy metabolism are among the putative functions of AHR. Challenges in AHR research include marked species differences, and cell, tissue and context dependence of AHR functions. The commentary is focused on AHR's role in the integration between energy expenditure and microbial and non-infectious inflammation, the latter exemplified by obesity-mediated nonalcoholic fatty liver disease. One of the mechanisms controlling energy-consuming inflammation is represented by a signalsome that is involved in retinoic acid-triggered neutrophil differentiation and regulation of the NADPH oxidase complex (NOX). Established signalsome components are AHR, CD38, multiple protein kinases and adaptors. To prevent chronic inflammatory diseases, the complex interplay between a range of inflammatory responses and energy expenditure must be precisely regulated. Surviving an infection requires both pathogen clearance and tissue protection from inflammatory damage. Defenses are energy-consuming anabolic programs. Therefore, anti-inflammatory, catabolic tolerance programs by metabolic reprogramming of macrophages have evolved. Therapeutic options of AHR agonists to reduce chronic inflammatory diseases are discussed.
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Affiliation(s)
- Karl Walter Bock
- Institute of Experimental and Clinical Pharmacology and Toxicology, Wilhelmstrasse 56, D-72074 Tübingen, Germany.
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