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Guo Y, Liu Z, Wang J, Deng X, He L, Zhang Y, Liu H, Qiu J. Equol neutralizes toxin B to combat Clostridioides difficile infection without disrupting the gut microbiota. Microbiol Res 2025; 298:128219. [PMID: 40378594 DOI: 10.1016/j.micres.2025.128219] [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: 03/14/2025] [Revised: 05/09/2025] [Accepted: 05/09/2025] [Indexed: 05/19/2025]
Abstract
Clostridioides difficile (C. difficile) toxin B (TcdB) is essential for C. difficile pathogenicity. TcdB induces apoptosis in host cells by internalizing and utilizing its glycosyltransferase activity to modify members of the small GTPase protein family through glycosylation. The intestinal environment is critical for the colonization of C. difficile, and the use of broad-spectrum antibiotics disrupts the balance of the gut microbiota, leading to increased susceptibility of the host to C. difficile. At present, the mainstream clinical approach for treating C. difficile infection (CDI) involves antibiotic therapies such as vancomycin, which disrupt the gut microbiota and are associated with a considerable risk of infection recurrence. Therefore, there is an urgent clinical need to develop new strategies to combat CDI. Here, we have identified a natural compound, equol, which inhibits the TcdB-mediated glycosylation of Rac1 through direct interaction, thereby reducing TcdB-induced cell death. Equol functions as an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO), effectively suppressing the conversion of tryptophan to kynurenine in the intestinal tract while preserving the integrity of the gut microbiota. Concurrently, equol exhibits robust antioxidant properties, which markedly reduced TcdB-mediated oxidative damage and subsequent cell death. These findings suggest that equol holds therapeutic potential for the treatment of CDI.
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Affiliation(s)
- Yan Guo
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Zhiying Liu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Jianfeng Wang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xuming Deng
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Liuqing He
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, China
| | - Yong Zhang
- Center for Pathogen Biology and Infectious Diseases, State Key Laboratory for Zoonotic Diseases, The First Hospital of Jilin University, Changchun, China.
| | - Hongtao Liu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
| | - Jiazhang Qiu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
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Hossen MM, Fleiss B, Zakaria R. The current state in liquid chromatography-mass spectrometry methods for quantifying kynurenine pathway metabolites in biological samples: a systematic review. Crit Rev Clin Lab Sci 2025:1-17. [PMID: 40302386 DOI: 10.1080/10408363.2025.2495160] [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: 11/11/2024] [Revised: 03/04/2025] [Accepted: 04/15/2025] [Indexed: 05/02/2025]
Abstract
Kynurenine pathway (KP) metabolites are implicated in various disorders, including Alzheimer's disease, schizophrenia, and adverse pregnancy outcomes. Simultaneous measurement of multiple KP metabolites offers valuable insight into the pathway's role in health and disease, would improve this relatively undeveloped field. This systematic review aim was to summarize the state of the art for measuring the eight key KP metabolites, using liquid chromatography-mass spectrometry (LC-MS), explicitly focusing on whether methods were validated using established guidelines with superior sensitivity and selectivity. We undertook a comprehensive review of the literature using the PRISMA guidelines. Our search uncovered 66 publications, and 39 qualified the defined key criteria. We summarized each publication's method development parameters, analytical design, and method performance specifications. We found notable variability in sample preparation techniques and analytical design across biological matrices, underscoring a lack of universally established and validated methods for KP metabolite quantification. We also identified significant gaps in the basic method evaluation. Our findings highlight that no single method has been evaluated for quantifying the eight key KP metabolites across three or more biological sample types, revealing a critical gap in the field. Our review emphasizes the need for robust analytical methods to quantify KP metabolites across multiple biological matrices, facilitating a better understanding of their roles in health and disease. Given the diversity of disorders involving the KP in the clinical testing lab, developing such methods will reduce diagnostic errors and advance KP metabolite research, supporting more precise, and personalized medical care.
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Affiliation(s)
- Md Munnaf Hossen
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Bobbi Fleiss
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
- Inserm, NeuroDiderot, Université Paris-Cité, Paris, France
| | - Rosita Zakaria
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
- Centre for Food and Allergy Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia
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3
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Fan Y, Li Y, Gu X, Chen N, Chen Y, Fang C, Wang Z, Yin Y, Deng H, Dai L. Intestinal metabolites in colitis-associated carcinogenesis: Building a bridge between host and microbiome. Chin Med J (Engl) 2025:00029330-990000000-01527. [PMID: 40287783 DOI: 10.1097/cm9.0000000000003430] [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: 11/18/2024] [Indexed: 04/29/2025] Open
Abstract
ABSTRACT Microbial-derived metabolites are important mediators of host-microbial interactions. In recent years, the role of intestinal microbial metabolites in colorectal cancer has attracted considerable attention. These metabolites, which can be derived from bacterial metabolism of dietary substrates, modification of host molecules such as bile acids, or directly from bacteria, strongly influence the progression of colitis-associated cancer (CAC) by regulating inflammation and immune response. Here, we review how microbiome metabolites short-chain fatty acids (SCFAs), secondary bile acids, polyamines, microbial tryptophan metabolites, and polyphenols are involved in the tumorigenesis and development of CAC through inflammation and immunity. Given the heated debate on the metabolites of microbiota in maintaining gut homeostasis, serving as tumor molecular markers, and affecting the efficacy of immune checkpoint inhibitors in recent years, strategies for the prevention and treatment of CAC by targeting intestinal microbial metabolites are also discussed in this review.
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Affiliation(s)
- Yating Fan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China
| | - Yang Li
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xiangshuai Gu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China
| | - Na Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China
- School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan 610500, China
| | - Ye Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China
| | - Chao Fang
- Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Ziqiang Wang
- Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yuan Yin
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Hongxin Deng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China
| | - Lei Dai
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China
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Ożga K, Stepuch P, Maciejewski R, Sadok I. Promising Gastric Cancer Biomarkers-Focus on Tryptophan Metabolism via the Kynurenine Pathway. Int J Mol Sci 2025; 26:3706. [PMID: 40332338 PMCID: PMC12027761 DOI: 10.3390/ijms26083706] [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: 02/28/2025] [Revised: 04/08/2025] [Accepted: 04/10/2025] [Indexed: 05/08/2025] Open
Abstract
Currently, gastric cancer treatment remains an enormous challenge and requires a multidisciplinary approach. Globally, the incidence and prevalence of gastric cancer vary, with the highest rates found in East Asia, Central Europe, and Eastern Europe. Early diagnosis is critical for successful surgical removal of gastric cancer, but the disease often develops asymptomatically. Therefore, many cases are diagnosed at an advanced stage, resulting in poor survival. Metastatic gastric cancer also has a poor prognosis. Therefore, it is urgent to identify reliable molecular disease markers and develop an effective medical treatment for advanced stages of the disease. This review summarizes potential prognostic or predictive markers of gastric cancer. Furthermore, the role of tryptophan metabolites from the kynurenine pathway as prognostic, predictive, and diagnostic factors of gastric cancer is discussed, as this metabolic pathway is associated with tumor immune resistance.
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Affiliation(s)
- Kinga Ożga
- Department of Biomedicine and Environmental Research, Institute of Biological Sciences, Faculty of Medicine, Collegium Medicum, The John Paul II Catholic University of Lublin, Konstantynów 1J, 20-708 Lublin, Poland;
| | - Paweł Stepuch
- II Department of Oncological Surgery with Subdivision of Minimal Invasive Surgery, Center of Oncology of the Lublin Region St. Jana z Dukli, Jaczewskiego 7, 20-090 Lublin, Poland;
| | - Ryszard Maciejewski
- Faculty of Medicine, Collegium Medicum, The John Paul II Catholic University of Lublin, Konstantynów 1H, 20-708 Lublin, Poland;
| | - Ilona Sadok
- Department of Biomedical and Analytical Chemistry, Institute of Biological Sciences, Faculty of Medicine, Collegium Medicum, The John Paul II Catholic University of Lublin, Konstantynów 1J, 20-708 Lublin, Poland
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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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Tejeda-Muñoz N, Binder G, Mei KC. Emerging therapeutic strategies for Wnt-dependent colon cancer targeting macropinocytosis. Cells Dev 2024; 180:203974. [PMID: 39528157 PMCID: PMC12009640 DOI: 10.1016/j.cdev.2024.203974] [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: 09/02/2024] [Revised: 11/06/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024]
Abstract
Aberrations in the Wnt signaling pathway, particularly mutations in genes like APC and β-catenin, are pivotal in initiating and driving the progression of colorectal cancer (CRC), establishing this pathway as a crucial target for therapeutic intervention. Membrane trafficking plays a key role in regulating Wnt signaling by controlling the activation, modulation, and secretion of essential signaling molecules that contribute to CRC progression. This review explores the connection between membrane trafficking and Wnt signaling, with a specific focus on macropinocytosis-an endocytic process involved in nutrient uptake that also plays a role in Wnt signal regulation. The relationship between Wnt signaling and macropinocytosis, critical in both embryonic development and cancer onset, reveals a new dimension for therapeutic intervention. Targeting Wnt signaling through the modulation of macropinocytosis and broader membrane trafficking pathways presents a promising therapeutic strategy, with several candidates already in early clinical trials. These emerging approaches underscore the potential of targeting Wnt and its associated membrane trafficking processes for CRC treatment, aligning with the development of innovative therapies.
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Affiliation(s)
- Nydia Tejeda-Muñoz
- Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Grace Binder
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles 90095-1662, USA
| | - Kuo-Ching Mei
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Binghamton, Binghamton, NY, USA
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7
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de Lima J, Leite JA, Basso PJ, Ghirotto B, Martins da Silva E, Menezes-Silva L, Hiyane MI, Goes CP, Coutinho LL, de Andrade Oliveira V, Olsen Saraiva Câmara N. Sirtuin 1 regulates the phenotype and functions of dendritic cells through Ido1 pathway in obesity. Cell Death Dis 2024; 15:757. [PMID: 39424786 PMCID: PMC11489582 DOI: 10.1038/s41419-024-07125-3] [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: 05/26/2024] [Revised: 09/09/2024] [Accepted: 10/01/2024] [Indexed: 10/21/2024]
Abstract
Sirtuin 1 (SIRT1) is a class III histone deacetylase (HDAC3) that plays a crucial role in regulating the activation and differentiation of dendritic cells (DCs) as well as controlling the polarization and activation of T cells. Obesity, a chronic inflammatory condition, is characterized by the activation of immune cells in various tissues. We hypothesized that SIRT1 might influence the phenotype and functions of DCs through the Ido1 pathway, ultimately leading to the polarization towards pro-inflammatory T cells in obesity. In our study, we observed that SIRT1 activity was reduced in bone marrow-derived DCs (BMDCs) from obese animals. These BMDCs exhibited elevated oxidative phosphorylation (OXPHOS) and increased extracellular acidification rates (ECAR), along with enhanced expression of class II MHC, CD86, and CD40, and elevated secretion of IL-12p40, while the production of TGF-β was reduced. The kynurenine pathway activity was decreased in BMDCs from obese animals, particularly under SIRT1 inhibition. SIRT1 positively regulated the expression of Ido1 in DCs in a PPARγ-dependent manner. To support these findings, ATAC-seq analysis revealed that BMDCs from obese mice had differentially regulated open chromatin regions compared to those from lean mice, with reduced chromatin accessibility at the Sirt1 genomic locus in BMDCs from obese WT mice. Gene Ontology (GO) enrichment analysis indicated that BMDCs from obese animals had disrupted metabolic pathways, including those related to GTPase activity and insulin response. Differential expression analysis showed reduced levels of Pparg and Sirt1 in BMDCs from obese mice, which was challenged and confirmed using BMDCs from mice with conditional knockout of Sirt1 in dendritic cells (SIRT1∆). This study highlights that SIRT1 controls the metabolism and functions of DCs through modulation of the kynurenine pathway, with significant implications for obesity-related inflammation.
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Affiliation(s)
- Jean de Lima
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Jefferson Antônio Leite
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Paulo José Basso
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Bruno Ghirotto
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Eloisa Martins da Silva
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Luisa Menezes-Silva
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Meire Ioshie Hiyane
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Carolina Purcell Goes
- Department of Animal Science, Luiz de Queiroz College of Agriculture (ESALQ), University of São Paulo, Piracicaba, Brazil
| | - Luiz Lehmann Coutinho
- Department of Animal Science, Luiz de Queiroz College of Agriculture (ESALQ), University of São Paulo, Piracicaba, Brazil
| | - Vinicius de Andrade Oliveira
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
- Center for Natural and Human Sciences, Federal University of ABC, Santo André, Brazil.
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Zhou A, Jia J, Ji X, Cheng S, Song X, Hu J, Zhao Y, Yu L, Wang J, Wang F. Reshaped Local and Systemic Immune Responses Triggered by a Biomimetic Multifunctional Nanoplatform Coordinating Multi-Pathways for Cancer Therapy. ACS APPLIED MATERIALS & INTERFACES 2024. [PMID: 39356986 DOI: 10.1021/acsami.4c05714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
Immunotherapy has fundamentally transformed the clinical cancer treatment landscape; however, achieving intricate and multifaceted modulation of the immune systems remains challenging. Here, a multipathway coordination of immunogenic cell death (ICD), autophagy, and indoleamine 2,3-dioxygenase-1 (IDO1) was achieved by a biomimetic nano-immunomodulator assembled from a chemotherapeutic agent (doxorubicin, DOX), small interfering RNA (siRNA) molecules targeting IDO1 (siIDO1), and the zeolitic imidazolate framework-8 (ZIF-8). After being camouflaged with a macrophage membrane, the biomimetic nanosystem, named mRDZ, enriched in tumors, which allowed synergistic actions of its components within tumor cells. The chemotherapeutic intervention led to a compensatory upregulation in the expression of IDO1, consequently exerting an inhibitory effect on the reactive oxygen species (ROS) and autophagic responses triggered by DOX and ZIF-8. Precise gene silencing of IDO1 by siIDO1 alleviated its suppressive influence, thereby facilitating increased ROS production and improved autophagy, ultimately bolstering tumor immunogenicity. mRDZ exhibited strong capability to boost potent local and systemic antitumor immune responses with a feature of memory, which led to the effective suppression of the growth, lung metastasis, and recurrence of the tumor. Serving as an exemplary model for the straightforward and potent reshaping of the immune system against tumors, mRDZ offers valuable insights into the development of immunomodulatory nanomaterials for cancer therapy.
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Affiliation(s)
- Ao Zhou
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
- Key Laboratory of Nanomedical Technology (Education Department of Fujian Province), Nanomedical Technology Research Institute, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China
| | - Jingyan Jia
- Key Laboratory of Nanomedical Technology (Education Department of Fujian Province), Nanomedical Technology Research Institute, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China
| | - Xueyang Ji
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
| | - Sunying Cheng
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
| | - Xiaoxin Song
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
| | - Jingyan Hu
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
| | - Yan Zhao
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
| | - Luying Yu
- Key Laboratory of Nanomedical Technology (Education Department of Fujian Province), Nanomedical Technology Research Institute, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China
| | - Jieting Wang
- Key Laboratory of Nanomedical Technology (Education Department of Fujian Province), Nanomedical Technology Research Institute, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China
| | - Fang Wang
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
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9
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Churchhouse AMD, Billard CV, Suzuki T, Pohl SÖG, Doleschall NJ, Donnelly K, Nixon C, Arends MJ, Din S, Kirkwood K, Marques Junior J, Von Kriegsheim A, Coffelt SB, Myant KB. Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression. Oncogene 2024; 43:3094-3107. [PMID: 39242821 PMCID: PMC11473400 DOI: 10.1038/s41388-024-03135-9] [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: 08/08/2023] [Revised: 08/05/2024] [Accepted: 08/13/2024] [Indexed: 09/09/2024]
Abstract
Inflammatory Bowel Disease-associated colorectal cancer (IBD-CRC) is a known and serious complication of Inflammatory Bowel Disease (IBD) affecting the colon. However, relatively little is known about the pathogenesis of IBD-associated colorectal cancer in comparison with its sporadic cancer counterpart. Here, we investigated the function of Dock2, a gene mutated in ~10% of IBD-associated colorectal cancers that encodes a guanine nucleotide exchange factor (GEF). Using a genetically engineered mouse model of IBD-CRC, we found that whole body loss of Dock2 increases tumourigenesis via immune dysregulation. Dock2-deficient tumours displayed increased levels of IFNγ-associated genes, including the tryptophan metabolising, immune modulatory enzyme, IDO1, when compared to Dock2-proficient tumours. This phenotype was driven by increased IFNγ-production in T cell populations, which infiltrated Dock2-deficient tumours, promoting IDO1 expression in tumour epithelial cells. We show that IDO1 inhibition delays tumourigenesis in Dock2 knockout mice, and we confirm that this pathway is conserved across species as IDO1 expression is elevated in human IBD-CRC and in sporadic CRC cases with mutated DOCK2. Together, these data demonstrate a previously unidentified tumour suppressive role of DOCK2 that limits IFNγ-induced IDO1 expression and cancer progression, opening potential new avenues for therapeutic intervention.
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Affiliation(s)
- Antonia M D Churchhouse
- Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK
| | - Caroline V Billard
- Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK
| | - Toshiyasu Suzuki
- Cancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Sebastian Ö G Pohl
- Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK
| | - Nora J Doleschall
- Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK
| | - Kevin Donnelly
- Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK
| | - Colin Nixon
- Cancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK
| | - Mark J Arends
- Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK
| | - Shahida Din
- Edinburgh IBD Unit, Western General Hospital, Edinburgh, UK
| | - Kathryn Kirkwood
- Department of Pathology, Western General Hospital, Edinburgh, UK
| | - Jair Marques Junior
- Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK
| | - Alex Von Kriegsheim
- Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK
| | - Seth B Coffelt
- Cancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Kevin B Myant
- Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital Campus, Edinburgh, UK.
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10
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Yang M, Cao M, Zhang X, Fu B, Chen Y, Tan Y, Xuan C, Su Y, Tan D, Hu R. IDO1 inhibitors are synergistic with CXCL10 agonists in inhibiting colon cancer growth. Biomed Pharmacother 2024; 179:117412. [PMID: 39255734 DOI: 10.1016/j.biopha.2024.117412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/29/2024] [Accepted: 09/04/2024] [Indexed: 09/12/2024] Open
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) is an immune checkpoint that degrades L-tryptophan to kynurenine (Kyn) and enhance immunosuppression, which can be an attractive target for treating colon cancer. IDO1 inhibitors have limited efficacy when used as monotherapies, and their combination approach has been shown to provide synergistic benefits. Many studies have shown that targeting chemokines can promote the efficacy of immune checkpoint inhibitors. Therefore, this study explored the use of IDO1 inhibitors with multiple chemokines to develop a new combination regimen for IDO1 inhibitors. We found that IDO1 inhibitors reduce the secretion of C-X-C motif ligand 10(CXCL10) in cancer cells, and CXCL10 supplementation significantly improved the anticancer effect of IDO1 inhibitors. The combination of the IDO1 inhibitor with CXCL10 or its agonist axitinib had a synergistic inhibitory effect on the growth of colon cancer cells and transplanted CT26 tumors. This synergistic effect may be achieved by inhibiting cancer cell proliferation, promoting cancer cell apoptosis, promoting CD8+T cell differentiation and decreasing Tregs. Two downstream pathways of IDO1 affect CXCL10 secretion. One being the Kyn-aryl hydrocarbon receptor (AHR) pathway, the other is the general control nonderepressible 2(GCN2). Our study provides a new reference for combination regimens of IDO1 inhibitors.
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Affiliation(s)
- Mengdi Yang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Mengran Cao
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xin Zhang
- School of Pharmacy, Anhui Medical University, Hefei 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei 230032, China
| | - Bin Fu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yaxin Chen
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yingying Tan
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Chenyuan Xuan
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yongren Su
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Dashan Tan
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Rong Hu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
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11
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Li Y, Li C, Yao X, Lv J, Li W, Fu R, Chen M, Yang P, Dai Q, Wei W, Li Z. IDO1-mediated kynurenine production inhibits IGFBP5 signaling to promote 5-fluorouracil-induced senescence escape and chemoresistance in colorectal cancer. Am J Cancer Res 2024; 14:4551-4566. [PMID: 39417170 PMCID: PMC11477834 DOI: 10.62347/xtrc3347] [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: 04/07/2024] [Accepted: 09/22/2024] [Indexed: 10/19/2024] Open
Abstract
Cellular senescence is an irreversible state of growth arrest, and induction of senescence is considered a potential therapeutic strategy against cancer. Indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme catabolizing L-tryptophan into kynurenine, plays a key role in tumor immune tolerance. However, the roles of IDO1 in cellular senescence and chemoresistance remain elusive. Herein, we observed a significant elevation of IDO1 expression in colorectal cancer (CRC) tissues compared to non-neoplastic controls, based on both the GEPIA database and mouse model. Functionally, ectopic expression of IDO1 blunted 5-fluorouracil (5-FU)-induced cell senescence and rendered CRC cells more refractory towards 5-FU treatment, whereas IDO1 silencing resulted in opposing effects. Further studies demonstrated that IDO1 overexpression decreased the levels of senescent-related proteins, including p16, p21, p53, and cyclin D1. Mechanistically, the kynurenine released from IDO1-expressing CRC cells inhibited the IGFBP5/p53 signaling pathway, accounting for IDO1-mediated suppression of cell senescence and induction of chemoresistance. Collectively, these data revealed an unrecognized role of IDO1 in senescence escape and chemoresistance via releasing its catabolite kynurenine, implicating that therapeutically targeting IDO1 or IGFBP5/p53 signaling pathway holds great promise for CRC treatment.
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Affiliation(s)
- Yu Li
- School of Life Science, Anhui Medical UniversityHefei 230032, Anhui, China
| | - Chao Li
- School of Life Science, Anhui Medical UniversityHefei 230032, Anhui, China
| | - Xufeng Yao
- School of Life Science, Anhui Medical UniversityHefei 230032, Anhui, China
| | - Junjie Lv
- Department of Oncology, The First Affiliated Hospital of Anhui Medical UniversityHefei 230022, Anhui, China
| | - Wenjun Li
- School of Life Science, Anhui Medical UniversityHefei 230032, Anhui, China
| | - Rong Fu
- School of Basic Medical Sciences, Shanxi Medical UniversityTaiyuan 030001, Shanxi, China
| | - Mengyang Chen
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi UniversityTaiyuan 030006, Shanxi, China
| | - Peng Yang
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi UniversityTaiyuan 030006, Shanxi, China
| | - Qian Dai
- School of Life Science, Anhui Medical UniversityHefei 230032, Anhui, China
| | - Wei Wei
- Department of Oncology, The First Affiliated Hospital of Anhui Medical UniversityHefei 230022, Anhui, China
| | - Zongwei Li
- School of Life Science, Anhui Medical UniversityHefei 230032, Anhui, China
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12
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Zhuo X, Deng H, Qiu M, Qiu X. Pathomic model based on histopathological features and machine learning to predict IDO1 status and its association with breast cancer prognosis. Breast Cancer Res Treat 2024; 207:151-165. [PMID: 38780888 PMCID: PMC11230954 DOI: 10.1007/s10549-024-07350-6] [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: 02/07/2024] [Accepted: 04/18/2024] [Indexed: 05/25/2024]
Abstract
PURPOSE To establish a pathomic model using histopathological image features for predicting indoleamine 2,3-dioxygenase 1 (IDO1) status and its relationship with overall survival (OS) in breast cancer. METHODS A pathomic model was constructed using machine learning and histopathological images obtained from The Cancer Genome Atlas database to predict IDO1 expression. The model performance was evaluated based on the area under the curve, calibration curve, and decision curve analysis (DCA). Prediction scores (PSes) were generated from the model and applied to divide the patients into two groups. Survival outcomes, gene set enrichment, immune microenvironment, and tumor mutations were assessed between the two groups. RESULTS Survival analysis followed by multivariate correction revealed that high IDO1 is a protective factor for OS. Further, the model was calibrated, and it exhibited good discrimination. Additionally, the DCA showed that the proposed model provided a good clinical net benefit. The Kaplan-Meier analysis revealed a positive correlation between high PS and improved OS. Univariate and multivariate Cox regression analyses demonstrated that PS is an independent protective factor for OS. Moreover, differentially expressed genes were enriched in various essential biological processes, including extracellular matrix receptor interaction, angiogenesis, transforming growth factor β signaling, epithelial mesenchymal transition, cell junction, tryptophan metabolism, and heme metabolic processes. PS was positively correlated with M1 macrophages, CD8 + T cells, T follicular helper cells, and tumor mutational burden. CONCLUSION These results indicate the potential ability of the proposed pathomic model to predict IDO1 status and the OS of breast cancer patients.
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Affiliation(s)
- Xiaohua Zhuo
- Department of Pathology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian, China
| | - Hailong Deng
- Department of Pathology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian, China
| | - Mingzhu Qiu
- Department of Pathology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian, China
| | - Xiaoming Qiu
- Department of Pathology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian, China.
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13
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Cheng Z, Fobian SF, Gurrieri E, Amin M, D'Agostino VG, Falahati M, Zalba S, Debets R, Garrido MJ, Saeed M, Seynhaeve ALB, Balcioglu HE, Ten Hagen TLM. Lipid-based nanosystems: the next generation of cancer immune therapy. J Hematol Oncol 2024; 17:53. [PMID: 39030582 PMCID: PMC11265205 DOI: 10.1186/s13045-024-01574-1] [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: 05/23/2024] [Accepted: 07/11/2024] [Indexed: 07/21/2024] Open
Abstract
Immunotherapy has become an important part of the oncotherapy arsenal. Its applicability in various cancer types is impressive, as well as its use of endogenous mechanisms to achieve desired ends. However, off-target or on-target-off-tumor toxicity, limited activity, lack of control in combination treatments and, especially for solid tumors, low local accumulation, have collectively limited clinical use thereof. These limitations are partially alleviated by delivery systems. Lipid-based nanoparticles (NPs) have emerged as revolutionary carriers due to favorable physicochemical characteristics, with specific applications and strengths particularly useful in immunotherapeutic agent delivery. The aim of this review is to highlight the challenges faced by immunotherapy and how lipid-based NPs have been, and may be further utilized to address such challenges. We discuss recent fundamental and clinical applications of NPs in a range of areas and provide a detailed discussion of the main obstacles in immune checkpoint inhibition therapies, adoptive cellular therapies, and cytokine therapies. We highlight how lipid-based nanosystems could address these through either delivery, direct modulation of the immune system, or targeting of the immunosuppressive tumor microenvironment. We explore advanced and emerging liposomal and lipid nanoparticle (LNP) systems for nucleic acid delivery, intrinsic and extrinsic stimulus-responsive formulations, and biomimetic lipid-based nanosystems in immunotherapy. Finally, we discuss the key challenges relating to the clinical use of lipid-based NP immunotherapies, suggesting future research directions for the near term to realize the potential of these innovative lipid-based nanosystems, as they become the crucial steppingstone towards the necessary enhancement of the efficacy of immunotherapy.
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Affiliation(s)
- Ziyun Cheng
- Precision Medicine in Oncology (PrMiO), Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands
- Nanomedicine Innovation Center Erasmus (NICE), Erasmus Medical Center, Rotterdam, The Netherlands
| | - Seth-Frerich Fobian
- Precision Medicine in Oncology (PrMiO), Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands
- Nanomedicine Innovation Center Erasmus (NICE), Erasmus Medical Center, Rotterdam, The Netherlands
| | - Elena Gurrieri
- Laboratory of Biotechnology and Nanomedicine, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
| | - Mohamadreza Amin
- Precision Medicine in Oncology (PrMiO), Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands
- Nanomedicine Innovation Center Erasmus (NICE), Erasmus Medical Center, Rotterdam, The Netherlands
| | - Vito Giuseppe D'Agostino
- Laboratory of Biotechnology and Nanomedicine, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
| | - Mojtaba Falahati
- Precision Medicine in Oncology (PrMiO), Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Sara Zalba
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Navarra Institute for Health Research, Pamplona, Spain
| | - Reno Debets
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands
| | - María J Garrido
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Navarra Institute for Health Research, Pamplona, Spain
| | - Mesha Saeed
- Precision Medicine in Oncology (PrMiO), Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Ann L B Seynhaeve
- Precision Medicine in Oncology (PrMiO), Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Hayri E Balcioglu
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
| | - Timo L M Ten Hagen
- Precision Medicine in Oncology (PrMiO), Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
- Nanomedicine Innovation Center Erasmus (NICE), Erasmus Medical Center, Rotterdam, The Netherlands.
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14
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Ge S, Wang L, Jin C, Xie H, Zheng G, Cui Z, Zhang C. Unveiling the neuroprotection effects of Volvalerenic acid A: Mitochondrial fusion induction via IDO1-mediated Stat3-Opa1 signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155555. [PMID: 38579641 DOI: 10.1016/j.phymed.2024.155555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 03/11/2024] [Accepted: 03/19/2024] [Indexed: 04/07/2024]
Abstract
BACKGROUND Ischemic stroke is a leading cause of death and long-term disability worldwide. Studies have suggested that cerebral ischemia induces massive mitochondrial damage. Valerianic acid A (VaA) is the main active ingredient of valerianic acid with neuroprotective activity. PURPOSE This study aimed to investigate the neuroprotective effects of VaA with ischemic stroke and explore the underlying mechanisms. METHOD In this study, we established the oxygen-glucose deprivation and reperfusion (OGD/R) cell model and the middle cerebral artery occlusion and reperfusion (MCAO/R) animal model in vitro and in vivo. Neurological behavior score, 2, 3, 5-triphenyl tetrazolium chloride (TTC) staining and Hematoxylin and Eosin (HE) Staining were used to detect the neuroprotection of VaA in MCAO/R rats. Also, the levels of ROS, mitochondrial membrane potential (MMP), and activities of NAD+ were detected to reflect mitochondrial function. Mechanistically, gene knockout experiments, transfection experiments, immunofluorescence, DARTS, and molecular dynamics simulation experiments showed that VaA bound to IDO1 regulated the kynurenine pathway of tryptophan metabolism and prevented Stat3 dephosphorylation, promoting Stat3 activation and subsequent transcription of the mitochondrial fusion-related gene Opa1. RESULTS We showed that VaA decreased the infarct volume in a dose-dependent manner and exerted neuroprotective effects against reperfusion injury. Furthermore, VaA promoted Opa1-related mitochondrial fusion and reversed neuronal mitochondrial damage and loss after reperfusion injury. In SH-SY5Y cells, VaA (5, 10, 20 μM) exerted similar protective effects against OGD/R-induced injury. We then examined the expression of significant enzymes regulating the kynurenine (Kyn) pathway of the ipsilateral brain tissue of the ischemic stroke rat model, and these enzymes may play essential roles in ischemic stroke. Furthermore, we found that VaA can bind to the initial rate-limiting enzyme IDO1 in the Kyn pathway and prevent Stat3 phosphorylation, promoting Stat3 activation and subsequent transcription of the mitochondrial fusion-related gene Opa1. Using in vivo IDO1 knockdown and in vitro IDO1 overexpressing models, we demonstrated that the promoted mitochondrial fusion and neuroprotective effects of VaA were IDO1-dependent. CONCLUSION VaA administration improved neurological function by promoting mitochondrial fusion through the IDO1-mediated Stat3-Opa1 pathway, indicating its potential as a therapeutic drug for ischemic stroke.
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Affiliation(s)
- Shanchun Ge
- Sino-Jan Joint Lab of Natural Health Products Research, School of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Lei Wang
- Sino-Jan Joint Lab of Natural Health Products Research, School of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Chang Jin
- Sino-Jan Joint Lab of Natural Health Products Research, School of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Haifeng Xie
- Research and Development Department, Chengdu Biopurify Phytochemicals Ltd., Chengdu, China
| | - Guoping Zheng
- Nanjing Hospital of Chinese Medicine Affiliated of Nanjing University of Chinese Medicine, Nanjing, 21000, China
| | - Zhengguo Cui
- Department of Environmental Health, University of Fukui School of Medical Sciences, 23-3 Matsuoka Shimoaizuki, Eiheiji, Fukui, 910-1193, Japan.
| | - Chaofeng Zhang
- Sino-Jan Joint Lab of Natural Health Products Research, School of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing, 211198, China.
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15
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Sun H, Li H, Guan Y, Yuan Y, Xu C, Fu D, Xie P, Li J, Zhao T, Wang X, Feng Y, Wang H, Gao S, Yang S, Shi Y, Liu J, Chang A, Huang C, Hao J. BICC1 drives pancreatic cancer stemness and chemoresistance by facilitating tryptophan metabolism. SCIENCE ADVANCES 2024; 10:eadj8650. [PMID: 38896624 PMCID: PMC11186499 DOI: 10.1126/sciadv.adj8650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 04/30/2024] [Indexed: 06/21/2024]
Abstract
Pancreatic adenocarcinoma is the fourth leading cause of malignancy-related deaths, with rapid development of drug resistance driven by pancreatic cancer stem cells. However, the mechanisms sustaining stemness and chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, we demonstrate that Bicaudal C homolog 1 (BICC1), an RNA binding protein regulating numerous cytoplasmic mRNAs, facilitates chemoresistance and stemness in PDAC. Mechanistically, BICC1 activated tryptophan catabolism in PDAC by up-regulating indoleamine 2,3-dioxygenase-1 (IDO1) expression, a tryptophan-catabolizing enzyme. Increased levels of tryptophan metabolites contribute to NAD+ synthesis and oxidative phosphorylation, leading to a stem cell-like phenotype. Blocking BICC1/IDO1/tryptophan metabolism signaling greatly improves the gemcitabine (GEM) efficacy in several PDAC models with high BICC1 level. These findings indicate that BICC1 is a critical tryptophan metabolism regulator that drives the stemness and chemoresistance of PDAC and thus a potential target for combinatorial therapeutic strategy against chemoresistance.
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MESH Headings
- Tryptophan/metabolism
- Humans
- Drug Resistance, Neoplasm/genetics
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/drug therapy
- Cell Line, Tumor
- Animals
- Mice
- Gene Expression Regulation, Neoplastic
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/genetics
- Gemcitabine
- Deoxycytidine/analogs & derivatives
- Deoxycytidine/pharmacology
- RNA-Binding Proteins/metabolism
- RNA-Binding Proteins/genetics
- Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
- Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics
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Affiliation(s)
- Huizhi Sun
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
| | - Hui Li
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
| | - Yuqi Guan
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
| | - Yudong Yuan
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
| | - Chao Xu
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
| | - Danqi Fu
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
| | - Peng Xie
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
| | - Jianming Li
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
| | - Tiansuo Zhao
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
| | - Xiuchao Wang
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
| | - Yukuan Feng
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
| | - Hongwei Wang
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
| | - Song Gao
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
| | - Shengyu Yang
- Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Yi Shi
- Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, P. R. China
| | - Jing Liu
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
| | - Antao Chang
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
| | - Chongbiao Huang
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
| | - Jihui Hao
- Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin, P. R. China
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16
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Huang Z, Dong J, Guo T, Jiang W, Hu R, Zhang S, Du T, Jiang X. TRIM28 Regulates Proliferation of Gastric Cancer Cells Partly Through SRF/IDO1 Axis. J Cancer 2024; 15:4417-4429. [PMID: 38947391 PMCID: PMC11212089 DOI: 10.7150/jca.95094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 05/14/2024] [Indexed: 07/02/2024] Open
Abstract
Background: Gastric cancer (GC) is one of the most common malignancies worldwide, with high incidence and mortality rate. Tripartite motif-containing 28 (TRIM28) is an important molecule that affects the occurrence and development of tumors, but its function in GC has not been elucidated clearly. The purpose of this study is to explore the molecular mechanism by which TRIM28 affect the GC. Methods: TRIM28 expression was tested in RNA-seq data from TCGA database, tumor tissue samples from patients and GC cell lines. Genes were silenced or overexpressed by siRNA, lentivirus-mediated shRNA, or plasmids. Cell Counting Kit-8 (CCK-8) and colony formation assays were performed to explore the proliferation of GC cells after TRIM28 knockdown. RNA-seq and TCGA database were used to identify target genes. Luciferase report assay was employed to detect the possible mechanism between TRIM28 and Indoleamine 2,3-dioxygenase (IDO1). Tryptophan concentration in cell supernatant was measured using a fluorometric assay kit. MGC-803 and 746T cells were injected into mice to establish xenograft animal models. Results: The expression of TRIM28 was positively correlated with tumor size and poorer prognosis. Upregulation of TRIM28 was observed in GC tissues and cells. In vitro, we proved that knockdown of TRIM28 significantly inhibited the proliferation of GC cells. Then TRIM28 was found to be positively correlated with the expression of IDO1 in GC cells. In accordance with this, tryptophan levels in cell supernatants were increased in TRIM28 knockdown GC cells and overexpression of IDO1 could reverse this phenotype. Serum response factor (SRF), a reported regulator of IDO1, was also regulated by TRIM28 in GC cells. And decreased expression of IDO1 induced by TRIM28 knockdown could be partly reversed through overexpression of serum response factor (SRF) in GC cells. Functional research demonstrated that the expression of IDO1 was increased in GC and IDO1 knockdown could also inhibited the proliferation of GC cells. Furthermore, overexpression of IDO1 could partly reverse proliferation inhibited by TRIM28 knockdown in GC cells. In vivo, knockdown of TRIM28 significantly inhibited the tumor growth and overexpression of IDO1 and SRF both could reverse proliferation inhibited by TRIM28 knockdown. Conclusions: TRIM28 is crucial in the development of GC, and may regulate IDO1 through SRF. TRIM28 promote GC cell proliferation through SRF/IDO1 axis.
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Affiliation(s)
- Zhiye Huang
- School of Medicine, Tongji University, Shanghai, 200092, China
- Department of Gastrointestinal surgery, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Jiaxing Dong
- School of Medicine, Tongji University, Shanghai, 200092, China
- Department of Gastrointestinal surgery, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Taohua Guo
- School of Medicine, Tongji University, Shanghai, 200092, China
- Department of Gastrointestinal surgery, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Wanju Jiang
- School of Medicine, Tongji University, Shanghai, 200092, China
- Department of Gastrointestinal surgery, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Renhao Hu
- School of Medicine, Tongji University, Shanghai, 200092, China
- Department of Gastrointestinal surgery, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Shun Zhang
- Department of Gastrointestinal surgery, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Tao Du
- Department of Gastrointestinal surgery, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Xiaohua Jiang
- Department of Gastrointestinal surgery, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
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17
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Ikuta T, Kanda H. Tumor formation at ileocecal junction associated with interleukin-1β upregulation in aryl hydrocarbon receptor-deficient mouse. J Biochem Mol Toxicol 2024; 38:e23736. [PMID: 38769691 DOI: 10.1002/jbt.23736] [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: 11/07/2023] [Revised: 03/22/2024] [Accepted: 05/09/2024] [Indexed: 05/22/2024]
Abstract
Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor. We previously reported spontaneous ileocecal tumorigenesis in AhR-deficient mice after the age of 10 weeks, which originated in the confined area between ileum and cecum. This study aimed to investigate the underlying mechanism that causes tumor development at this particular location. To observe mucosal architecture in detail, tissues of ileocecal region were stained with methylene blue. Gene expression profile in the ileocecal tissue was compared with cecum. Immunohistochemical analysis was performed with ileocecal tissues using antibodies against ileum-specific Reg3β or cecum-specific Pitx2. In AhR+/+ mice and AhR+/- mice, that do not develop lesions, methylene blue staining revealed the gradually changing shape and arrangement of villi from ileum to cecum. It was also observed in AhR-deficient mice before developing lesions. Microarray-based analysis revealed abundant antimicrobial genes, such as Reg3, in the ileocecal tissue while FGFR2 and Pitx2 were specific to cecum. Immunohistochemical analysis of AhR-deficient mice indicated that lesions originated from the ileocecal junction, a boundary area between different epithelial types. Site-specific gene expression analysis revealed higher expression of IL-1β at the ileocecal junction compared with the ileum or cecum of 9-11-week-old AhR-deficient mice. These findings indicate that AhR plays a vital function in the ileocecal junction. Regulating AhR activity can potentially manage the stability of ileocecal tissue possessing cancer-prone characteristics. This investigation contributes to understanding homeostasis in different epithelial transitional tissues, frequently associated with pathological states.
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Affiliation(s)
- Togo Ikuta
- Department of Cancer Prevention, Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan
| | - Hiroaki Kanda
- Department of Pathology, Saitama Cancer Center, Saitama, Japan
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18
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Soltani-Asl M, Azimnasab-Sorkhabi P, Yoshinaga TT, de Oliveira Massoco C, Kfoury JR. The combination of IDO and AHR blockers reduces the migration and clonogenicity of breast cancer cells. Immunol Res 2024; 72:430-437. [PMID: 38153625 DOI: 10.1007/s12026-023-09450-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 12/21/2023] [Indexed: 12/29/2023]
Abstract
The indoleamine-2,3-dioxygenase (IDO) enzyme causes immunosuppressive consequences in the tumor microenvironment (TME). In addition, the role of aryl hydrocarbon receptor (AHR) in the TME is under discussion. The current study evaluated the role of the IDO and AHR blockers on cell migration, clonogenic, and IDO expression of murine breast cancer cells. The cell migration and clonogenic abilities of breast cancer cells are evaluated by wound‑healing assay (cell migration assay) and Colony formation assay (clonogenic assay). Also, flow cytometry analysis was used to detect the IDO-positive breast cancer cells. The results showed that treating cells with a combination of IDO and AHR blockers dramatically reduced breast cancer cells' migration and clonogenic capacities. Treating cells with only AHR blockade suppressed the clonogenic rate. Since both IDO and AHR are involved in their complex molecular networks, blocking both IDO and AHR might cause alterations in their molecular networks resulting in diminishing the migration and clonogenic abilities of breast cancer cells. However, further investigations are required to confirm our findings within in vivo models as a novel therapy for breast cancer.
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Affiliation(s)
- Maryam Soltani-Asl
- Department of Surgery, School of Veterinary Medicine and Animal Sciences, University of Sao Paulo, Sao Paulo, Brazil.
| | - Parviz Azimnasab-Sorkhabi
- Department of Surgery, School of Veterinary Medicine and Animal Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Tulio Teruo Yoshinaga
- Department of Surgery, School of Veterinary Medicine and Animal Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Cristina de Oliveira Massoco
- Department of Pathology, School of Veterinary Medicine and Animal Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Jose Roberto Kfoury
- Department of Surgery, School of Veterinary Medicine and Animal Sciences, University of Sao Paulo, Sao Paulo, Brazil
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19
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Kondo T, Okada Y, Shizuya S, Yamaguchi N, Hatakeyama S, Maruyama K. Neuroimmune modulation by tryptophan derivatives in neurological and inflammatory disorders. Eur J Cell Biol 2024; 103:151418. [PMID: 38729083 DOI: 10.1016/j.ejcb.2024.151418] [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: 12/25/2023] [Revised: 05/02/2024] [Accepted: 05/03/2024] [Indexed: 05/12/2024] Open
Abstract
The nervous and immune systems are highly developed, and each performs specialized physiological functions. However, they work together, and their dysfunction is associated with various diseases. Specialized molecules, such as neurotransmitters, cytokines, and more general metabolites, are essential for the appropriate regulation of both systems. Tryptophan, an essential amino acid, is converted into functional molecules such as serotonin and kynurenine, both of which play important roles in the nervous and immune systems. The role of kynurenine metabolites in neurodegenerative and psychiatric diseases has recently received particular attention. Recently, we found that hyperactivity of the kynurenine pathway is a critical risk factor for septic shock. In this review, we first outline neuroimmune interactions and tryptophan derivatives and then summarized the changes in tryptophan metabolism in neurological disorders. Finally, we discuss the potential of tryptophan derivatives as therapeutic targets for neuroimmune disorders.
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Affiliation(s)
- Takeshi Kondo
- Department of Biochemistry, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido 060-8636, Japan
| | - Yuka Okada
- Department of Ophthalmology, Wakayama Medical University School of Medicine, Wakayama 641-0012, Japan
| | - Saika Shizuya
- Department of Ophthalmology, Wakayama Medical University School of Medicine, Wakayama 641-0012, Japan
| | - Naoko Yamaguchi
- Department of Pharmacology, School of Medicine, Aichi Medical University, Aichi 480-1195, Japan
| | - Shigetsugu Hatakeyama
- Department of Biochemistry, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido 060-8636, Japan
| | - Kenta Maruyama
- Department of Pharmacology, School of Medicine, Aichi Medical University, Aichi 480-1195, Japan.
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20
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Nkandeu DS, Joubert AM, Serem JC, Bipath P, Hlophe YN. An exploratory study on the effect of kynurenine metabolites on sEnd-2 endothelioma cells. Cell Biochem Funct 2024; 42:e4065. [PMID: 38807444 DOI: 10.1002/cbf.4065] [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: 03/05/2024] [Revised: 05/14/2024] [Accepted: 05/18/2024] [Indexed: 05/30/2024]
Abstract
Cancer is the second leading cause of mortality worldwide. The development of anticancer therapy plays a crucial role in mitigating tumour progression and metastasis. Epithelioid hemangioendothelioma is a very rare cancer, however, with a high systemic involvement. Kynurenine metabolites which include l-kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid have been shown to inhibit T-cell proliferation resulting in a decrease in cell growth of natural killer cells and T cells. Furthermore, metabolites such as l-kynurenine have been shown to inhibit proliferation of melanoma cells in vitro. Considering these metabolite properties, the present study aimed to explore the in vitro effects of l-kynurenine, quinolinic acid and kynurenic acid on endothelioma sEnd-2 cells and on endothelial (EA. hy926 cells) (control cell line). The in vitro effect at 24, 48, and 72 h exposure to a range of 1-4 mM of the respective kynurenine metabolites on the two cell lines in terms of cell morphology, cell cycle progression and induction of apoptosis was assessed. The half inhibitory concentration (IC50), as determined using nonlinear regression, for l-kynurenine, quinolinic acid and kynurenic acid was 9.17, 15.56, and 535.40 mM, respectively. Optical transmitted light differential interference contrast and hematoxylin and eosin staining revealed cells blocked in metaphase, formation of apoptotic bodies and compromised cell density in l-kynurenine-treated cells. A statistically significant increase in the number of cells present in the sub-G1 phase was observed in l-kynurenine-treated sample. To our knowledge, this was the first in vitro study conducted to investigate the mechanism of action of kynurenine metabolites on endothelioma sEnd-2 cells. It can be concluded that l-kynurenine exerts an antiproliferative effect on the endothelioma sEnd-2 cell line by decreasing cell growth and proliferation as well as a metaphase block. These hallmarks suggest cell death via apoptosis. Further research will be conducted on l-kynurenine to assess the effect on cell adhesion in vitro and in vivo as cell-cell adhesion has been shown to increase metastasis to distant organs therefore, the inhibition of adhesion may lead to a decrease in metastasis.
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Affiliation(s)
- Danielle Sandra Nkandeu
- Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Anna Margaretha Joubert
- Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - June Cheptoo Serem
- Department of Anatomy, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Priyesh Bipath
- Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Yvette Nkondo Hlophe
- Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
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21
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Huang J, Wang X, Li N, Fan W, Li X, Zhou Q, Liu J, Li W, Zhang Z, Liu X, Zeng S, Yang H, Tian M, Yang P, Hou S. YY1 Lactylation Aggravates Autoimmune Uveitis by Enhancing Microglial Functions via Inflammatory Genes. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2308031. [PMID: 38493498 PMCID: PMC11109619 DOI: 10.1002/advs.202308031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 03/02/2024] [Indexed: 03/19/2024]
Abstract
Activated microglia in the retina are essential for the development of autoimmune uveitis. Yin-Yang 1 (YY1) is an important transcription factor that participates in multiple inflammatory and immune-mediated diseases. Here, an increased YY1 lactylation in retinal microglia within in the experimental autoimmune uveitis (EAU) group is observed. YY1 lactylation contributed to boosting microglial activation and promoting their proliferation and migration abilities. Inhibition of lactylation suppressed microglial activation and attenuated inflammation in EAU. Mechanistically, cleavage under targets & tagmentation （CUT&Tag） analysis revealed that YY1 lactylation promoted microglial activation by regulating the transcription of a set of inflammatory genes, including STAT3, CCL5, IRF1, IDO1, and SEMA4D. In addition, p300 is identified as the writer of YY1 lactylation. Inhibition of p300 decreased YY1 lactylation and suppressed microglial inflammation in vivo and in vitro. Collectively, the results showed that YY1 lactylation promoted microglial dysfunction in autoimmune uveitis by upregulating inflammatory cytokine secretion and boosting cell migration and proliferation. Therapeutic effects can be achieved by targeting the lactate/p300/YY1 lactylation/inflammatory genes axis.
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Affiliation(s)
- Jiaxing Huang
- Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute; Chongqing Branch of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
| | - Xiaotang Wang
- Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute; Chongqing Branch of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
| | - Na Li
- Department of Laboratory Medicine, Beijing Tongren HospitalCapital Medical UniversityBeijing100005China
| | - Wei Fan
- Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute; Chongqing Branch of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
| | - Xingran Li
- Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute; Chongqing Branch of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
| | - Qian Zhou
- Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute; Chongqing Branch of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
| | - Jiangyi Liu
- Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute; Chongqing Branch of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
| | - Wanqian Li
- Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute; Chongqing Branch of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
| | - Zhi Zhang
- Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute; Chongqing Branch of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
| | - Xiaoyan Liu
- Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute; Chongqing Branch of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
| | - Shuhao Zeng
- Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute; Chongqing Branch of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
| | - Hui Yang
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren HospitalCapital Medical UniversityBeijing100730China
| | - Meng Tian
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren HospitalCapital Medical UniversityBeijing100730China
| | - Peizeng Yang
- Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute; Chongqing Branch of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China
| | - Shengping Hou
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren HospitalCapital Medical UniversityBeijing100730China
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22
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Yu L, Lu J, Du W. Tryptophan metabolism in digestive system tumors: unraveling the pathways and implications. Cell Commun Signal 2024; 22:174. [PMID: 38462620 PMCID: PMC10926624 DOI: 10.1186/s12964-024-01552-7] [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: 12/10/2023] [Accepted: 03/01/2024] [Indexed: 03/12/2024] Open
Abstract
Tryptophan (Trp) metabolism plays a crucial role in influencing the development of digestive system tumors. Dysregulation of Trp and its metabolites has been identified in various digestive system cancers, including esophageal, gastric, liver, colorectal, and pancreatic cancers. Aberrantly expressed Trp metabolites are associated with diverse clinical features in digestive system tumors. Moreover, the levels of these metabolites can serve as prognostic indicators and predictors of recurrence risk in patients with digestive system tumors. Trp metabolites exert their influence on tumor growth and metastasis through multiple mechanisms, including immune evasion, angiogenesis promotion, and drug resistance enhancement. Suppressing the expression of key enzymes in Trp metabolism can reduce the accumulation of these metabolites, effectively impacting their role in the promotion of tumor progression and metastasis. Strategies targeting Trp metabolism through specific enzyme inhibitors or tailored drugs exhibit considerable promise in enhancing therapeutic outcomes for digestive system tumors. In addition, integrating these approaches with immunotherapy holds the potential to further enhance treatment efficacy.
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Affiliation(s)
- Liang Yu
- State Key Laboratory for Diagnosis, Treatment of Infectious Diseases,, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China
| | - Juan Lu
- State Key Laboratory for Diagnosis, Treatment of Infectious Diseases,, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China.
| | - Weibo Du
- State Key Laboratory for Diagnosis, Treatment of Infectious Diseases,, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China.
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23
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Dobrovolskienė N, Balevičius R, Mlynska A, Žilionytė K, Aleksander Krasko J, Strioga M, Lieknina I, Pjanova D, Pašukonienė V. Immunomodulatory properties of bacteriophage derived dsRNA of different size and their use as anticancer vaccine adjuvants. Vaccine 2024; 42:512-521. [PMID: 38184395 DOI: 10.1016/j.vaccine.2023.12.071] [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: 10/04/2023] [Revised: 12/14/2023] [Accepted: 12/21/2023] [Indexed: 01/08/2024]
Abstract
Dendritic cell (DC) based immunotherapy is one of the strategies to combat cancer invoking a patient's immune system. This form of anticancer immunotherapy employs adjuvants to enhance the immune response, triggering mechanisms of innate immunity and thus increase immunotherapeutic efficiency. A conventional adjuvant for DCs maturation during production of anticancer vaccines is bacterial LPS. Nevertheless, synthetic dsRNAs were also shown to stimulate different receptors on innate immune cells and to activate immune responses through induction of cytokines via toll-like receptors. In our study we investigated the potential of Larifan as dsRNA of natural origin to stimulate maturation of DCs with proinflammatory (possible antitumoral) activity and to compare these immunostimulatory properties between Larifan's fractions with different molecular lengths. To explore the suitability of this product for therapy, it is necessary to study the properties of its different fractions and compare them to standard adjuvants. We investigated the effect of Larifan's fractions on immune system stimulation in vivo by monitoring the survival time of tumor-bearing mice. Murine DCs produced in vitro using Larifan and its fractions together with tumor antigens during production were also characterized. All Larifan fractions resulted in inducing high expression of immunogenic markers CD40, CD80, CD86, CCR7, MHC II and lower secretion of the immunosuppressive cytokine IL-10, compared to the maturation with LPS in mDCs. The lowest expression of tolerogenic gene Ido1 and highest expression of the immunogenic genes Clec7a, Tnf, Icosl, Il12rb2, Cd209a were characteristic to the unfractionated dsRNA and short fraction FR15. In the mouse model the best overall survival rate was observed in mice treated with medium-length FR9 and FR15. We can state that both Larifan and its fractions were superior to LPS as vaccine adjuvants in stimulating phenotype and functional activity of mature DCs. DCs maturation using these factors induces a valuable anticancer immune response.
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Affiliation(s)
- Neringa Dobrovolskienė
- Laboratory of Immunology, National Cancer Institute, Santariškių g. 1, LT-08660 Vilnius, Lithuania.
| | - Ramojus Balevičius
- Life Sciences Center, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, Lithuania.
| | - Agata Mlynska
- Laboratory of Immunology, National Cancer Institute, Santariškių g. 1, LT-08660 Vilnius, Lithuania; Department of Chemistry and Bioengineering, Vilnius Gediminas Technical University, Saulėtekio al. 11, LT-10223 Vilnius, Lithuania.
| | - Karolina Žilionytė
- Laboratory of Immunology, National Cancer Institute, Santariškių g. 1, LT-08660 Vilnius, Lithuania.
| | - Jan Aleksander Krasko
- Laboratory of Immunology, National Cancer Institute, Santariškių g. 1, LT-08660 Vilnius, Lithuania; Department of Chemistry and Bioengineering, Vilnius Gediminas Technical University, Saulėtekio al. 11, LT-10223 Vilnius, Lithuania.
| | - Marius Strioga
- Laboratory of Immunology, National Cancer Institute, Santariškių g. 1, LT-08660 Vilnius, Lithuania
| | - Ilva Lieknina
- Latvian Biomedical Research and Study Centre, Ratsupites Street 1, Riga LV-1067, Latvia.
| | - Dace Pjanova
- Latvian Biomedical Research and Study Centre, Ratsupites Street 1, Riga LV-1067, Latvia; Riga Stradins University, Ratsupites street 5., Riga LV-1067, Latvia.
| | - Vita Pašukonienė
- Laboratory of Immunology, National Cancer Institute, Santariškių g. 1, LT-08660 Vilnius, Lithuania; Department of Chemistry and Bioengineering, Vilnius Gediminas Technical University, Saulėtekio al. 11, LT-10223 Vilnius, Lithuania.
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24
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Kwiatkowska I, Hermanowicz JM, Czarnomysy R, Surażyński A, Kowalczuk K, Kałafut J, Przybyszewska-Podstawka A, Bielawski K, Rivero-Müller A, Mojzych M, Pawlak D. Assessment of an Anticancer Effect of the Simultaneous Administration of MM-129 and Indoximod in the Colorectal Cancer Model. Cancers (Basel) 2023; 16:122. [PMID: 38201550 PMCID: PMC10778160 DOI: 10.3390/cancers16010122] [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: 11/24/2023] [Revised: 12/20/2023] [Accepted: 12/23/2023] [Indexed: 01/12/2024] Open
Abstract
(1) Background: The purpose of the given study was to examine the antitumor activity of the simultaneous administration of MM-129, a 1,2,4-triazine derivative, and indoximod (IND), the kynurenine pathway inhibitor, toward colon cancer. (2) Methods: The efficiency of the co-administration of the studied compounds was assessed in xenografted zebrafish embryos. Then, the effects of the combined administration of compounds on cellular processes such as cell viability, apoptosis, and intracellular signaling pathways were evaluated. In vitro studies were performed using two colorectal cancer cell lines, namely, DLD-1 and HT-29. (3) Results: The results indicated that the simultaneous application of MM-129 and indoximod induced a stronger inhibition of tumor growth in zebrafish xenografts. The combination of these compounds intensified the process of apoptosis by lowering the mitochondrial potential, enhancing the externalization of phosphatidylserine (PS) and activation of caspases. Additionally, the expression of protein kinase B (AKT) and indoleamine 2,3-dioxygenase-(1IDO1) was disrupted under the applied compound combination. (4) Conclusions: Simultaneous targeting of ongoing cell signaling that promotes tumor progression, along with inhibition of the kynurenine pathway enzyme IDO1, results in the enhancement of the antitumor effect of the tested compounds against the colon cancer cells.
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Affiliation(s)
- Iwona Kwiatkowska
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (J.M.H.); (D.P.)
| | - Justyna Magdalena Hermanowicz
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (J.M.H.); (D.P.)
- Department of Clinical Pharmacy, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland
| | - Robert Czarnomysy
- Department of Synthesis and Technology of Drugs, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (R.C.); (K.B.)
| | - Arkadiusz Surażyński
- Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland;
| | - Krystyna Kowalczuk
- Department of Integrated Medical Care, Medical University of Bialystok, ul. M Skłodowskiej-Curie 7A, 15-096 Bialystok, Poland;
| | - Joanna Kałafut
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland; (J.K.); (A.P.-P.); (A.R.-M.)
| | - Alicja Przybyszewska-Podstawka
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland; (J.K.); (A.P.-P.); (A.R.-M.)
| | - Krzysztof Bielawski
- Department of Synthesis and Technology of Drugs, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (R.C.); (K.B.)
| | - Adolfo Rivero-Müller
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland; (J.K.); (A.P.-P.); (A.R.-M.)
| | - Mariusz Mojzych
- Faculty of Health Science, Collegium Medicum, The Mazovian Academy in Plock, Plac Dabrowskiego 2, 09-402 Plock, Poland;
| | - Dariusz Pawlak
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (J.M.H.); (D.P.)
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25
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Lim CK. Does maintaining a "healthy" tryptophan metabolism hold the key to cancer survivorship? Am J Clin Nutr 2023; 118:843-846. [PMID: 37923497 DOI: 10.1016/j.ajcnut.2023.09.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 09/14/2023] [Accepted: 09/15/2023] [Indexed: 11/07/2023] Open
Affiliation(s)
- Chai K Lim
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, North Ryde, New South Wales, Australia.
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26
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Xue C, Li G, Zheng Q, Gu X, Shi Q, Su Y, Chu Q, Yuan X, Bao Z, Lu J, Li L. Tryptophan metabolism in health and disease. Cell Metab 2023; 35:1304-1326. [PMID: 37352864 DOI: 10.1016/j.cmet.2023.06.004] [Citation(s) in RCA: 293] [Impact Index Per Article: 146.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 04/10/2023] [Accepted: 06/05/2023] [Indexed: 06/25/2023]
Abstract
Tryptophan (Trp) metabolism primarily involves the kynurenine, 5-hydroxytryptamine, and indole pathways. A variety of bioactive compounds produced via Trp metabolism can regulate various physiological functions, including inflammation, metabolism, immune responses, and neurological function. Emerging evidence supports an intimate relationship between Trp metabolism disorder and diseases. The levels or ratios of Trp metabolites are significantly associated with many clinical features. Additionally, studies have shown that disease progression can be controlled by modulating Trp metabolism. Indoleamine-2,3-dioxygenase, Trp-2,3-dioxygenase, kynurenine-3-monooxygenase, and Trp hydroxylase are the rate-limiting enzymes that are critical for Trp metabolism. These key regulatory enzymes can be targeted for treating several diseases, including tumors. These findings provide novel insights into the treatment of diseases. In this review, we have summarized the recent research progress on the role of Trp metabolites in health and disease along with their clinical applications.
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Affiliation(s)
- Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ganglei Li
- Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qiuxian Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xinyu Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yuanshuai Su
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Zhengyi Bao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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Wu M, Hao S, Wang X, Su S, Du S, Zhou S, Yang R, Du H. A pyroptosis-related gene signature that predicts immune infiltration and prognosis in colon cancer. Front Oncol 2023; 13:1173181. [PMID: 37503314 PMCID: PMC10369052 DOI: 10.3389/fonc.2023.1173181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 06/23/2023] [Indexed: 07/29/2023] Open
Abstract
Background Colon cancer (CC) is a highly heterogeneous malignancy associated with high morbidity and mortality. Pyroptosis is a type of programmed cell death characterized by an inflammatory response that can affect the tumor immune microenvironment and has potential prognostic and therapeutic value. The aim of this study was to evaluate the association between pyroptosis-related gene (PRG) expression and CC. Methods Based on the expression profiles of PRGs, we classified CC samples from The Cancer Gene Atlas and Gene Expression Omnibus databases into different clusters by unsupervised clustering analysis. The best prognostic signature was screened and established using least absolute shrinkage and selection operator (LASSO) and multivariate COX regression analyses. Subsequently, a nomogram was established based on multivariate COX regression analysis. Next, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed to explore the potential molecular mechanisms between the high- and low-risk groups and to explore the differences in clinicopathological characteristics, gene mutation characteristics, abundance of infiltrating immune cells, and immune microenvironment between the two groups. We also evaluated the association between common immune checkpoints and drug sensitivity using risk scores. The immunohistochemistry staining was utilized to confirm the expression of the selected genes in the prognostic model in CC. Results The 1163 CC samples were divided into two clusters (clusters A and B) based on the expression profiles of the 33 PRGs. Genes with prognostic value were screened from the DEGs between the two clusters, and an eight PRGs prognostic model was constructed. GSEA and GSVA of the high- and low-risk groups revealed that they were mainly enriched in inflammatory response-related pathways. Compared to those in the low-risk group, patients in the high-risk group had worse overall survival, an immunosuppressive microenvironment, and worse sensitivity to immunotherapy and drug treatment. Conclusion Our findings provide a foundation for future research targeting pyroptosis and new insights into prognosis and immunotherapy from the perspective of pyroptosis in CC.
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Affiliation(s)
- Mingjian Wu
- Department of Gastrointestinal Surgery, Panyu Maternal and Child Care Service Centre of Guangzhou (He Xian Memorial Affiliated Hospital of Southern Medical University), Guangzhou, China
| | - Shuai Hao
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xiaoxiang Wang
- The First Clinical Medical College, Guangdong Medical University, Zhanjiang, Zhanjiang, Guangdong, China
| | - Shuguang Su
- Department of Pathology, Panyu Maternal and Child Care Service Centre of Guangzhou (He Xian Memorial Affiliated Hospital of Southern Medical University), Guangzhou, China
| | - Siyuan Du
- Department of Pathology, Panyu Maternal and Child Care Service Centre of Guangzhou (He Xian Memorial Affiliated Hospital of Southern Medical University), Guangzhou, China
| | - Sitong Zhou
- Department of Dermatology, The First People’s Hospital of Foshan, Foshan, Guangdong, China
| | - Ronghua Yang
- Department of Burn and Plastic Surgery, Guangzhou First People’s Hospital, South China University of Technology, Guangzhou, Guangdong, China
| | - Hanpeng Du
- Department of Gastrointestinal Surgery, Panyu Maternal and Child Care Service Centre of Guangzhou (He Xian Memorial Affiliated Hospital of Southern Medical University), Guangzhou, China
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Cao W, Pan J, Mo K, Wang Z, Wei S, Yin Y, Qin M, Zhang W. Effects of gene silencing of indoleamine 2,3-dioxygenase 1 combined with rosmarinic acid on tumor immune microenvironment in H22 tumor-bearing mice. Int Immunopharmacol 2023; 119:110193. [PMID: 37062258 DOI: 10.1016/j.intimp.2023.110193] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 04/04/2023] [Accepted: 04/10/2023] [Indexed: 04/18/2023]
Abstract
Rosmarinic acid (RA) is a natural polyphenolic compound with several pharmacological activities, including immunomodulation and anti-tumor effect. Indoleamine 2,3-dioxygenase-1 (IDO1), the rate-limiting enzyme that metabolizes tryptophan into kynurenine, is an important negative immune regulator. This study aimed to explore the effect of combined action of IDO1 gene silencing and RA on tumor immune microenvironment. H22 tumor-bearing mice were treated with combination therapy with RA and IDO1-shRNA. The percentages and apoptosis of T-cells and subsets of splenic regulatory T-cells (Tregs) were detected by flow cytometry. Levels of tumor necrosis factor (TNF-α), Interferon-γ (IFN-γ), interleukin-2 (IL-2) and interleukin-10 (IL-10) were measured by enzyme linked immunosorbent assay (ELISA). Treatment with RA + IDO1-shRNA significantly increased the percentage of CD4+ T cells, ratio of CD4+/CD8+ and the levels of IFN-γ and IL-2, while decreased CD8+ apoptosis, the proportion of splenic Tregs and the levels of TNF-α and IL-10. The present study demonstrated that combination therapy with RA and IDO1-shRNA had anti-tumor effects on HCC. The mechanism might be related to regulating immune response and immunocytokines, as well as alleviating immunosuppression induced by Tregs in the tumor immune microenvironment.
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Affiliation(s)
- Wen Cao
- Department of Pharmacy, Guangxi International Zhuang Medicine Hospital, Nanning, Guangxi 530200, China.
| | - Jinfeng Pan
- Department of Pharmacy, Guangxi International Zhuang Medicine Hospital, Nanning, Guangxi 530200, China
| | - Kai Mo
- Department of Pharmacy, Nanning First People's Hospital, Nanning, Guangxi 530022, China
| | - Zhenning Wang
- Department of Pharmacy, Guangxi International Zhuang Medicine Hospital, Nanning, Guangxi 530200, China
| | - Sijun Wei
- Department of Pharmacy, Guangxi International Zhuang Medicine Hospital, Nanning, Guangxi 530200, China
| | - Yuan Yin
- Department of Pharmacy, Guangxi International Zhuang Medicine Hospital, Nanning, Guangxi 530200, China
| | - Mengyao Qin
- Department of Pharmacy, Guangxi International Zhuang Medicine Hospital, Nanning, Guangxi 530200, China
| | - Wenjuan Zhang
- Department of Pharmacy, Guangxi International Zhuang Medicine Hospital, Nanning, Guangxi 530200, China
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Zhang J, Zou S, Fang L. Metabolic reprogramming in colorectal cancer: regulatory networks and therapy. Cell Biosci 2023; 13:25. [PMID: 36755301 PMCID: PMC9906896 DOI: 10.1186/s13578-023-00977-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 02/01/2023] [Indexed: 02/10/2023] Open
Abstract
With high prevalence and mortality, together with metabolic reprogramming, colorectal cancer is a leading cause of cancer-related death. Metabolic reprogramming gives tumors the capacity for long-term cell proliferation, making it a distinguishing feature of cancer. Energy and intermediate metabolites produced by metabolic reprogramming fuel the rapid growth of cancer cells. Aberrant metabolic enzyme-mediated tumor metabolism is regulated at multiple levels. Notably, tumor metabolism is affected by nutrient levels, cell interactions, and transcriptional and posttranscriptional regulation. Understanding the crosstalk between metabolic enzymes and colorectal carcinogenesis factors is particularly important to advance research for targeted cancer therapy strategies via the investigation into the aberrant regulation of metabolic pathways. Hence, the abnormal roles and regulation of metabolic enzymes in recent years are reviewed in this paper, which provides an overview of targeted inhibitors for targeting metabolic enzymes in colorectal cancer that have been identified through tumor research or clinical trials.
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Affiliation(s)
- Jieping Zhang
- grid.12981.330000 0001 2360 039XDepartment of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuanchun Er Heng Road, Guangzhou, 510655 Guangdong China ,Guangdong Institute of Gastroenterology, Guangzhou, 510655 China
| | - Shaomin Zou
- grid.12981.330000 0001 2360 039XDepartment of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuanchun Er Heng Road, Guangzhou, 510655 Guangdong China ,Guangdong Institute of Gastroenterology, Guangzhou, 510655 China
| | - Lekun Fang
- Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuanchun Er Heng Road, Guangzhou, 510655, Guangdong, China. .,Guangdong Institute of Gastroenterology, Guangzhou, 510655, China.
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PPARs and the Kynurenine Pathway in Melanoma-Potential Biological Interactions. Int J Mol Sci 2023; 24:ijms24043114. [PMID: 36834531 PMCID: PMC9960262 DOI: 10.3390/ijms24043114] [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: 12/27/2022] [Revised: 01/28/2023] [Accepted: 02/01/2023] [Indexed: 02/08/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in various physiological and pathological processes within the skin. PPARs regulate several processes in one of the most aggressive skin cancers, melanoma, including proliferation, cell cycle, metabolic homeostasis, cell death, and metastasis. In this review, we focused not only on the biological activity of PPAR isoforms in melanoma initiation, progression, and metastasis but also on potential biological interactions between the PPAR signaling and the kynurenine pathways. The kynurenine pathway is a major pathway of tryptophan metabolism leading to nicotinamide adenine dinucleotide (NAD+) production. Importantly, various tryptophan metabolites exert biological activity toward cancer cells, including melanoma. Previous studies confirmed the functional relationship between PPAR and the kynurenine pathway in skeletal muscles. Despite the fact this interaction has not been reported in melanoma to date, some bioinformatics data and biological activity of PPAR ligands and tryptophan metabolites may suggest a potential involvement of these metabolic and signaling pathways in melanoma initiation, progression, and metastasis. Importantly, the possible relationship between the PPAR signaling pathway and the kynurenine pathway may relate not only to the direct biological effect on melanoma cells but also to the tumor microenvironment and the immune system.
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31
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Wang K, Ye K, Zhang X, Wang T, Qi Z, Wang Y, Jiang S, Zhang K. Dual Nicotinamide Phosphoribosyltransferase (NAMPT) and Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors for the Treatment of Drug-Resistant Nonsmall-Cell Lung Cancer. J Med Chem 2023; 66:1027-1047. [PMID: 36595482 DOI: 10.1021/acs.jmedchem.2c01954] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Depleting NAD+ by blocking its biosynthesis has emerged as an attractive anticancer strategy. Simultaneous blockade of NAD+ production from the salvage and de novo synthesis pathways by targeting NAMPT and IDO1 could achieve more effective NAD+ reduction and, subsequently, more robust antitumor efficacy. Herein, we report the discovery of the first series of dual NAMPT and IDO1 inhibitors according to multitarget drug rationales. Compound 10e has good and balanced inhibitory potencies against NAMPT and IDO1, and significantly inhibits both proliferation and migration of a NSCLC cell line resistant to taxol and FK866 (A549/R cells). Compound 10e also displays potent antitumor efficacy in A549/R xenograft mouse models with no significant toxicity. Moreover, this compound enhances the susceptibility of A549/R cells to taxol in vitro and in vivo. This work provides an efficient approach to targeting NAD+ metabolism in the area of cancer therapy, especially in the context of drug resistance.
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Affiliation(s)
- Kaizhen Wang
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Ke Ye
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xiangyu Zhang
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Tianyu Wang
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Zhihao Qi
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Youjun Wang
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Sheng Jiang
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Kuojun Zhang
- State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
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Ai D, Wang M, Zhang Q, Cheng L, Wang Y, Liu X, Xia LC. Regularized survival learning and cross-database analysis enabled identification of colorectal cancer prognosis-related immune genes. Front Genet 2023; 14:1148470. [PMID: 36911403 PMCID: PMC9995717 DOI: 10.3389/fgene.2023.1148470] [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: 01/20/2023] [Accepted: 02/13/2023] [Indexed: 02/25/2023] Open
Abstract
Colon adenocarcinoma is the most common type of colorectal cancer. The prognosis of advanced colorectal cancer patients who received treatment is still very poor. Therefore, identifying new biomarkers for prognosis prediction has important significance for improving treatment strategies. However, the power of biomarker analyses was limited by the used sample size of individual database. In this study, we combined Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases to expand the number of healthy tissue samples. We screened differentially expressed genes between the GTEx healthy samples and TCGA tumor samples. Subsequently, we applied least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox analysis to identify nine prognosis-related immune genes: ANGPTL4, IDO1, NOX1, CXCL3, LTB4R, IL1RL2, CD72, NOS2, and NUDT6. We computed the risk scores of samples based on the expression levels of these genes and divided patients into high- and low-risk groups according to this risk score. Survival analysis results showed a significant difference in survival rate between the two risk groups. The high-risk group had a significantly lower overall survival rate and poorer prognosis. We found the receiver operating characteristic based on the risk score was showed to accurately predict patients' prognosis. These prognosis-related immune genes may be potential biomarkers for colorectal cancer diagnosis and treatment. Our open-source code is freely available from GitHub at https://github.com/gutmicrobes/Prognosis-model.git.
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Affiliation(s)
- Dongmei Ai
- School of Mathematics and Physics, University of Science and Technology Beijing, Beijing, China
| | - Mingmei Wang
- School of Mathematics and Physics, University of Science and Technology Beijing, Beijing, China
| | - Qingchuan Zhang
- National Engineering Laboratory for Agri-Product Quality Traceability, Beijing Technology and Business University, Beijing, China
| | - Longwei Cheng
- School of Mathematics and Physics, University of Science and Technology Beijing, Beijing, China
| | - Yishu Wang
- School of Mathematics and Physics, University of Science and Technology Beijing, Beijing, China
| | - Xiuqin Liu
- School of Mathematics and Physics, University of Science and Technology Beijing, Beijing, China
| | - Li C Xia
- School of Mathematics, South China University of Technology, Guangzhou, China
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Zhang D, Ning J, Ramprasath T, Yu C, Zheng X, Song P, Xie Z, Zou MH. Kynurenine promotes neonatal heart regeneration by stimulating cardiomyocyte proliferation and cardiac angiogenesis. Nat Commun 2022; 13:6371. [PMID: 36289221 PMCID: PMC9606021 DOI: 10.1038/s41467-022-33734-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 09/29/2022] [Indexed: 12/25/2022] Open
Abstract
Indoleamine 2,3 dioxygenase-1 (IDO1) catalyzes tryptophan-kynurenine metabolism in many inflammatory and cancer diseases. Of note, acute inflammation that occurs immediately after heart injury is essential for neonatal cardiomyocyte proliferation and heart regeneration. However, the IDO1-catalyzed tryptophan metabolism during heart regeneration is largely unexplored. Here, we find that apical neonatal mouse heart resection surgery led to rapid and consistent increases in cardiac IDO1 expression and kynurenine accumulation. Cardiac deletion of Ido1 gene or chemical inhibition of IDO1 impairs heart regeneration. Mechanistically, elevated kynurenine triggers cardiomyocyte proliferation by activating the cytoplasmic aryl hydrocarbon receptor-SRC-YAP/ERK pathway. In addition, cardiomyocyte-derived kynurenine transports to endothelial cells and stimulates cardiac angiogenesis by promoting aryl hydrocarbon receptor nuclear translocation and enhancing vascular endothelial growth factor A expression. Notably, Ahr deletion prevents indoleamine 2,3 dioxygenase -kynurenine-associated heart regeneration. In summary, increasing indoleamine 2,3 dioxygenase-derived kynurenine level promotes cardiac regeneration by functioning as an endogenous regulator of cardiomyocyte proliferation and cardiac angiogenesis.
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Affiliation(s)
- Donghong Zhang
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street North East, Atlanta, GA, 30303, USA
| | - Jinfeng Ning
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street North East, Atlanta, GA, 30303, USA
| | - Tharmarajan Ramprasath
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street North East, Atlanta, GA, 30303, USA
| | - Changjiang Yu
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street North East, Atlanta, GA, 30303, USA
| | - Xiaoxu Zheng
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street North East, Atlanta, GA, 30303, USA
| | - Ping Song
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street North East, Atlanta, GA, 30303, USA
| | - Zhonglin Xie
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street North East, Atlanta, GA, 30303, USA
| | - Ming-Hui Zou
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street North East, Atlanta, GA, 30303, USA.
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Astragaloside IV Inhibits the Proliferation of Human Uterine Leiomyomas by Targeting IDO1. Cancers (Basel) 2022; 14:cancers14184424. [PMID: 36139584 PMCID: PMC9496999 DOI: 10.3390/cancers14184424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/05/2022] [Accepted: 09/08/2022] [Indexed: 11/27/2022] Open
Abstract
Simple Summary Immunotherapy is increasingly becoming a success strategy for oncology treatment. Indoleamine-2,3-dioxygenase1 (IDO1) is a tryptophan-degrading enzyme involved in immunological escape mechanisms, which is considered as a potential target for tumor therapy. However, the clinical efficacy of IDO1 inhibitors is not promising. Therefore, there is an urgent to investigate the mechanism between chemical drugs with antitumor effects and IDO1-mediated immunosuppression. The Chinese medicine AS-IV exerts antitumor effects with many advantages, including fewer toxic side effects and immunomodulatory effects. We noted the lack of studies of AS-IV on benign tumors. Therefore, our study demonstrates the Inhibitory effect of AS-IV on ULMs and elucidates the underlying mechanism. Abstract Astragaloside IV (AS-IV) is a chemical found in traditional Chinese medicine called Astragalus membranaceus (Fisch.) Bunge that has antitumor properties. However, the roles and mechanisms of AS-IV in uterine leiomyomas (ULMs) are unclear. The immunosuppressive enzyme indoleamine-2,3-dioxygenase-1 (IDO1) is involved in tumor formation. IDO1 is a new and reliable prognostic indicator for several cancers. In this work, AS-IV was applied to ULM cells in various concentrations. CCK-8, immunofluorescence, and flow cytometry were used to examine the proliferation and apoptosis of ULM cells caused by AS-IV. After lentiviral vector transduction with IDO1 short hairpin RNA (shRNA), the knockdown and overexpression of IDO1 were stable in ULM cells. To verify the antitumor effect of AS-IV in vivo, we established a rat model of uterine leiomyoma. HE staining, Masson staining, and transmission electron microscopy were used to observe pathological changes in the uterus, and the levels of serum sex hormones were measured by radio immune assay (RIA). The levels of CD3+T, CD4+T, and CD25+ Foxp3+Treg in rat peripheral blood were detected by flow cytometry. Western blotting and immunohistochemistry were used to examine protein expression. We found that AS-IV dramatically increased the apoptotic rate of ULM cells and reduced viability in a time- and dosage-dependent manner. After sh-IDO1 lentiviral transfection, we discovered that knocking down IDO1 reversed the effects of AS-IV on ULM cell proliferation and autophagy. We also found that AS-IV can effectively inhibit the growth of ULMs in vivo. AS-IV may promote apoptosis and autophagy in ULMs by activating PTEN/PI3K/AKT signaling through inhibition of IDO1. These findings imply that AS-IV exerts antifibroid effects, and the underlying mechanism may be IDO1, which is involved in proliferation, apoptosis, and autophagy.
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Li CC, Ye F, Xu CX, Chang Q, Liu XM, Pan RL. Effect of Radix Polygalae extract on the colonic dysfunction in rats induced by chronic restraint stress. JOURNAL OF ETHNOPHARMACOLOGY 2022; 294:115349. [PMID: 35533914 DOI: 10.1016/j.jep.2022.115349] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 04/28/2022] [Accepted: 05/03/2022] [Indexed: 06/14/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Radix Polygalae, a commonly used traditional Chinese herb, has conventionally functioned in tranquilization and sedation, where anti-inflammation may be the underlying mechanism. AIM OF THE STUDY Chronic restraint stress (CRS), a risk factor for the etiology of intestinal disorders, was used in the present study to examine whether Radix Polygalae extract (RPE) could modulate colonic dysfunction in CRS rats. MATERIALS AND METHODS Wistar rats were exposed to 28-day CRS (6 h daily), and RPE (135 mg/kg and 270 mg/kg) was intragastrically administered 1 h before CRS. Subsequently, the gut microbiota was determined using metagenomic sequencing. Colonic proinflammatory interleukin-1β, -6, and -18 were assayed using qRT-PCR and ELISA. Tight junction proteins were quantified by qRT-PCR and western blotting (WB), and tryptophan metabolic enzymes and metabolites were determined using qRT-PCR and UFLC-QTRAP-5500/MS. Moreover, protein expression of colonic tight junction proteins, NF-κB-NLRP3 signaling involved in the underlying mechanism of RPE were detected by WB. RESULTS RPE significantly decreased proinflammatory cytokines and reshaped the gut microbiota, especially the probiotics, including Lactobacillus and Bacteroides. Moreover, RPE could modulate the metabolite contents and enzyme expression associated with colonic tryptophan-kynurenine (TRP-KYN) metabolism and could increase tight junction protein expression in CRS rats. Furthermore, RPE inhibited the activation of NF-κB-NLRP3 signaling in the colon of CRS rats. CONCLUSION RPE could modulate colonic inflammation, colonic microbiota, tight junction, TRP-KYN metabolism and NF-κB-NLRP3 signaling to reach a colonic balance of CRS rats. The present study helped us to better understand and appreciate the various beneficial effects of RPE.
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Affiliation(s)
- Chen-Chen Li
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China
| | - Fan Ye
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China
| | - Chen-Xi Xu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China
| | - Qi Chang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China
| | - Xin-Min Liu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China.
| | - Rui-Le Pan
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China.
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Dual-target inhibitors of indoleamine 2, 3 dioxygenase 1 (Ido1): A promising direction in cancer immunotherapy. Eur J Med Chem 2022; 238:114524. [PMID: 35696861 DOI: 10.1016/j.ejmech.2022.114524] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 02/08/2023]
Abstract
Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that catalyzes the kynurenine (Kyn) pathway of tryptophan metabolism in the first step, and the kynurenine pathway plays a fundamental role in immunosuppression in the tumor microenvironment. Therefore, researchers are vigorously developing IDO1 inhibitors, hoping to apply them to cancer immunotherapy. Nowadays, there have been 11 kinds of IDO1 inhibitors entering clinical trials, among which many inhibitors have shown good tumor inhibitory effect in phase I/II clinical trials. But the phase III study of the most promising IDO1 inhibitor compound 29 (Epacadostat) failed in 2018, which may be caused by the compensation effect offered by tryptophan 2,3-dioxygenase (TDO), the mismatched drug combination strategies, or other reasons. Luckily, dual-target inhibitors show great potential and advantages in solving these problems. In recent years, many studies have linked IDO1 to popular targets and selected many IDO1 dual-target inhibitors through pharmacophore fusion strategy and library construction, which enhance the tumor inhibitory effect and reduce side effects. Currently, three kinds of IDO1/TDO dual-target inhibitors have entered clinical trials, and extensive studies have been developing on IDO1 dual-target inhibitors. In this review, we summarize the IDO1 dual-target inhibitors developed in recent years and focus on the structure optimization process, structure-activity relationship, and the efficacy of in vitro and in vivo experiments, shedding a light on the pivotal significance of IDO1 dual-target inhibitors in the treatment of cancer, providing inspiration for the development of new IDO1 dual-target inhibitors.
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Abd El-Fattah EE. IDO/kynurenine pathway in cancer: possible therapeutic approaches. Lab Invest 2022; 20:347. [PMID: 35918736 PMCID: PMC9344609 DOI: 10.1186/s12967-022-03554-w] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 07/25/2022] [Indexed: 11/10/2022]
Abstract
Cancer is one of the leading causes of death in both men and women worldwide. One of the main changes associated with cancer progression, metastasis, recurrence, and chemoresistance is the change in the tumor immune microenvironment, especially immunosuppression. Cancer immunosuppression appears in multiple forms, such as inhibition of immuno-stimulant cells with downregulation of immuno-stimulant mediators or through stimulation of immuno-suppressive cells with upregulation of immunosuppressive mediators. One of the most immunosuppressive mediators that approved potency in lung cancer progression is indoleamine 2,3-dioxygenase (IDO) and its metabolite kynurenine (Kyn). The current review tries to elucidate the role of IDO/Kyn on cancer proliferation, apoptosis, angiogenesis, oxidative stress, and cancer stemness. Besides, our review investigates the new therapeutic modalities that target IDO/Kyn pathway and thus as drug candidates for targeting lung cancer and drugs that potentiate IDO/Kyn pathway and thus can be cancer-promoting agents.
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Affiliation(s)
- Eslam E Abd El-Fattah
- Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.
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Jiang X, Jiang Z, Jiang M, Sun Y. Berberine as a Potential Agent for the Treatment of Colorectal Cancer. Front Med (Lausanne) 2022; 9:886996. [PMID: 35572960 PMCID: PMC9096113 DOI: 10.3389/fmed.2022.886996] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 03/29/2022] [Indexed: 01/10/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed and deadly malignancies worldwide. The incidence of CRC has been increasing, especially in young people. Although great advances have been made in managing CRC, the prognosis is unfavorable. Numerous studies have shown that berberine (BBR) is a safe and effective agent presenting significant antitumor effects. Nevertheless, the detailed underlying mechanism in treating CRC remains indistinct. In this review, we herein offer beneficial evidence for the utilization of BBR in the management and treatment of CRC, and describe the underlying mechanism(s). The review emphasizes several therapeutic effects of BBR and confirms that BBR could suppress CRC by modulating gene expression, the cell cycle, the inflammatory response, oxidative stress, and several signaling pathways. In addition, BBR also displays antitumor effects in CRC by regulating the gut microbiota and mucosal barrier function. This review emphasizes BBR as a potentially effective and safe drug for CRC therapy.
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Affiliation(s)
- Xi Jiang
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhongxiu Jiang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Min Jiang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yan Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Yan Sun
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Zhang Q, Li W. Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy. World J Stem Cells 2022; 14:267-286. [PMID: 35662861 PMCID: PMC9136564 DOI: 10.4252/wjsc.v14.i4.267] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/19/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.
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Affiliation(s)
- Qi Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wei Li
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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Zhang Z, Yu PF, Gu GL, Zhang YH, Wang YM, Dong ZW, Yang HR. Diffuse invasive signet ring cell carcinoma in total colorectum caused by ulcerative colitis: A case report and review of literature. World J Clin Cases 2022; 10:1729-1737. [PMID: 35211616 PMCID: PMC8855258 DOI: 10.12998/wjcc.v10.i5.1729] [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: 10/15/2021] [Revised: 12/05/2021] [Accepted: 12/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diffuse invasive signet ring cell carcinoma of the colorectum is extremely rare clinically. This type of colorectal cancer has certain clinical, pathological and biological characteristics that are different from ordinary colorectal cancer. CASE SUMMARY A 31-year-old young woman was admitted to the hospital for nearly 1 wk due to recurrent symptoms of mucopurulent bloody stools and abdominal distension. Preoperative colonoscopy showed a ring-shaped intestinal wall mass 10 cm from the rectum to the anus. Three pieces of tumor tissue were removed for examination. The pathological results showed rectal mucinous adenocarcinoma. The patient underwent laparoscopic exploration under general anesthesia, and then laparoscopic total colorectal resection, ileal pouch-anal anastomosis and ileostomy were performed. The patient was switched to a FOLFOX + cetuximab regimen. After the fifth cycle, the patient was unable to tolerate further treatment due to tumor progression and multiple organ dysfunction, and died at the end of May 2020. Overall survival was 7 mo. CONCLUSION Carcinogenesis of ulcerative colitis is different from sporadic colon cancer, and the overall prognosis is extremely poor.
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Affiliation(s)
- Zhi Zhang
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Beijing 100142, China
| | - Peng-Fei Yu
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Beijing 100142, China
| | - Guo-Li Gu
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Beijing 100142, China
| | - Yu-Hui Zhang
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Beijing 100142, China
- Graduate School, Hebei North University, Zhangjiakou 075000, Hebei Province, China
| | - Yu-Ming Wang
- Health Team, 93656 Troop of Chinese People's Liberation Army, Beijing 101113, China
| | - Zhi-Wei Dong
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Beijing 100142, China
| | - Hai-Rui Yang
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Beijing 100142, China
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Hou H, Chen D, Zhang K, Zhang W, Liu T, Wang S, Dai X, Wang B, Zhong W, Cao H. Gut microbiota-derived short-chain fatty acids and colorectal cancer: Ready for clinical translation? Cancer Lett 2022; 526:225-235. [PMID: 34843863 DOI: 10.1016/j.canlet.2021.11.027] [Citation(s) in RCA: 127] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 10/28/2021] [Accepted: 11/22/2021] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. It involves the complex interactions between genetic factors, environmental exposure, and gut microbiota. Specific changes in the gut microbiome and metabolome have been described in CRC, supporting the critical role of gut microbiota dysbiosis and microbiota-related metabolites in the tumorigenesis process. Short-chain fatty acids (SCFAs), the principal metabolites generated from the gut microbial fermentation of insoluble dietary fiber, can directly activate G-protein-coupled receptors (GPCRs), inhibit histone deacetylases (HDACs), and serve as energy substrates to connect dietary patterns and gut microbiota, thereby improving the intestinal health. A significantly lower abundance of SCFAs and SCFA-producing bacteria has been demonstrated in CRC, and the supplementation of SCFA-producing probiotics can inhibit intestinal tumor development. SCFAs-guided modulation in both mouse and human CRC models augmented their responses to chemotherapy and immunotherapy. This review briefly summarizes the complex crosstalk between SCFAs and CRC, which might inspire new approaches for the diagnosis, treatment and prevention of CRC on the basis of gut microbiota-derived metabolites SCFAs.
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Affiliation(s)
- Huiqin Hou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Danfeng Chen
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Kexin Zhang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Wanru Zhang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Tianyu Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Sinan Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Xin Dai
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Weilong Zhong
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
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Luby A, Alves-Guerra MC. Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy. Cancers (Basel) 2021; 13:5912. [PMID: 34885023 PMCID: PMC8656934 DOI: 10.3390/cancers13235912] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/17/2021] [Accepted: 11/19/2021] [Indexed: 12/18/2022] Open
Abstract
Over the past decade, advances in cancer immunotherapy through PD1-PDL1 and CTLA4 immune checkpoint blockade have revolutionized the management of cancer treatment. However, these treatments are inefficient for many cancers, and unfortunately, few patients respond to these treatments. Indeed, altered metabolic pathways in the tumor play a pivotal role in tumor growth and immune response. Thus, the immunosuppressive tumor microenvironment (TME) reprograms the behavior of immune cells by altering their cellular machinery and nutrient availability to limit antitumor functions. Today, thanks to a better understanding of cancer metabolism, immunometabolism and immune checkpoint evasion, the development of new therapeutic approaches targeting the energy metabolism of cancer or immune cells greatly improve the efficacy of immunotherapy in different cancer models. Herein, we highlight the changes in metabolic pathways that regulate the differentiation of pro- and antitumor immune cells and how TME-induced metabolic stress impedes their antitumor activity. Finally, we propose some drug strategies to target these pathways in the context of cancer immunotherapy.
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Hon KW, Zainal Abidin SA, Othman I, Naidu R. The Crosstalk Between Signaling Pathways and Cancer Metabolism in Colorectal Cancer. Front Pharmacol 2021; 12:768861. [PMID: 34887764 PMCID: PMC8650587 DOI: 10.3389/fphar.2021.768861] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/05/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Metabolic reprogramming represents an important cancer hallmark in CRC. Reprogramming core metabolic pathways in cancer cells, such as glycolysis, glutaminolysis, oxidative phosphorylation, and lipid metabolism, is essential to increase energy production and biosynthesis of precursors required to support tumor initiation and progression. Accumulating evidence demonstrates that activation of oncogenes and loss of tumor suppressor genes regulate metabolic reprogramming through the downstream signaling pathways. Protein kinases, such as AKT and c-MYC, are the integral components that facilitate the crosstalk between signaling pathways and metabolic pathways in CRC. This review provides an insight into the crosstalk between signaling pathways and metabolic reprogramming in CRC. Targeting CRC metabolism could open a new avenue for developing CRC therapy by discovering metabolic inhibitors and repurposing protein kinase inhibitors/monoclonal antibodies.
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Affiliation(s)
| | | | | | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Malaysia
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Chen CT, Wu PH, Hu CC, Nien HC, Wang JT, Sheu JC, Chow LP. Aberrant Upregulation of Indoleamine 2,3-Dioxygenase 1 Promotes Proliferation and Metastasis of Hepatocellular Carcinoma Cells via Coordinated Activation of AhR and β-Catenin Signaling. Int J Mol Sci 2021; 22:ijms222111661. [PMID: 34769098 PMCID: PMC8583706 DOI: 10.3390/ijms222111661] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 10/15/2021] [Accepted: 10/25/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Chronic liver inflammation due to hepatitis virus infection and other major effectors is a major risk factor of HCC. Indoleamine 2,3-dioxygenase 1 (IDO1), a heme enzyme highly expressed upon stimulation with proinflammatory cytokines such as interferon-γ (IFN-γ), is activated to modulate the tumor microenvironment and potentially crucial in the development of certain cancer types. Earlier studies have majorly reported an immunomodulatory function of IDO1. However, the specific role of IDO1 in cancer cells, particularly HCC, remains to be clarified. Analysis of The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA LIHC) dataset in the current study revealed a significant correlation between IDO1 expression and HCC. We further established inducible IDO1-expressing cell models by coupling lentivirus-mediated knockdown and IFN-γ induction of IDO1 in normal and HCC cells. In functional assays, proliferation and motility-related functions of HCC cells were compromised upon suppression of IDO1, which may partially be rescued by its enzymatic product, kynurenine (KYN), while normal hepatocytes were not affected. Aryl hydrocarbon receptor (AhR), a reported endogenous KYN receptor, is suggested to participate in tumorigenesis. In mechanistic studies, IDO1 activation promoted both AhR and β-catenin activity and nuclear translocation. Immunofluorescence staining and co-immunoprecipitation assays further disclosed interactions between AhR and β-catenin. In addition, we identified a Src-PTEN-PI3K/Akt-GSK-3β axis involved in β-catenin stabilization and activation following IDO1-mediated AhR activation. IDO1-induced AhR and β-catenin modulated the expression of proliferation- and EMT-related genes to facilitate growth and metastasis of HCC cells. Our collective findings provide a mechanistic basis for the design of more efficacious IDO1-targeted therapy for HCC.
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Affiliation(s)
- Chih-Ta Chen
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Rd, Taipei 100, Taiwan; (C.-T.C.); (P.-H.W.); (C.-C.H.)
| | - Pei-Hua Wu
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Rd, Taipei 100, Taiwan; (C.-T.C.); (P.-H.W.); (C.-C.H.)
| | - Chia-Chi Hu
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Rd, Taipei 100, Taiwan; (C.-T.C.); (P.-H.W.); (C.-C.H.)
| | - Hsiao-Ching Nien
- Department of Family Medicine, National Taiwan University Hospital, Taipei 100, Taiwan;
- Liver Disease Prevention and Treatment Research Foundation, Taipei 100, Taiwan;
| | - Jin-Town Wang
- Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Jin-Chuan Sheu
- Liver Disease Prevention and Treatment Research Foundation, Taipei 100, Taiwan;
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Lu-Ping Chow
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Rd, Taipei 100, Taiwan; (C.-T.C.); (P.-H.W.); (C.-C.H.)
- Correspondence: ; Tel.: +886-223-123-456 (ext. 88214); Fax: +886-223-958-814
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Gu Z, Pei W, Shen Y, Wang L, Zhu J, Zhang Y, Fan S, Wu Q, Li L, Zhang Z. Akkermansia muciniphila and its outer protein Amuc_1100 regulates tryptophan metabolism in colitis. Food Funct 2021; 12:10184-10195. [PMID: 34532729 DOI: 10.1039/d1fo02172a] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Dietary interventions, including dietary ingredients, nutrients and probiotics, exert anti-inflammatory effects in ulcerative colitis (UC). Our previous study showed that Akkermansia muciniphila (Akk), a promising probiotic, could protect against colitis via the regulation of the immune response. However, whether it can restore aberrant tryptophan (Trp) metabolism during colitis remains unclear. In this study, untargeted serum metabolomics of patients with UC and colitis mice showed that Trp metabolism was activated, which was confirmed by quantification of Trp metabolites from a validation cohort and animal study. Integrative analysis of faecal metagenomes and serum metabolomes revealed significant associations between Akk and three Trp metabolites. Live Akk, pasteurised Akk and Amuc_1100 failed to restore the reduction in Trp metabolites involved in the serotonin pathway in colitis mice. However, live Akk, pasteurised Akk and Amuc_1100 increased kynurenine (Kyn) but decreased 2-picolinic acid (PIC) levels and the PIC/Kyn ratio without regulating any of the genes involved in Trp metabolism, suggesting that they could suppress the Kyn pathway (KP) independent of colon tissue. In addition, they could significantly restore the enrichment of Trp metabolism mediated by faecal microbiota. Specifically, live Akk, pasteurised Akk and Amuc_1100 could significantly offset the reduction in indoleacetic acid (IAA) levels. Pasteurised Akk significantly elevated the serum levels of indole acrylic acid (IA). In addition, live Akk, pasteurised Akk and Amuc_1100 could upregulate aryl hydrocarbon receptor (AhR) targeted genes, including CYP1A1, IL-10 and IL-22, suggesting that Akk could activate AhR signaling by regulating Trp metabolism, thereby attenuating colonic inflammation.
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Affiliation(s)
- Zhenyang Gu
- Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P.R. China.
| | - Wenlong Pei
- Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P.R. China.
| | - Yonghua Shen
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P. R. China
| | - Lijuan Wang
- Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P.R. China.
| | - Jun Zhu
- Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P.R. China.
| | - Yi Zhang
- Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P.R. China.
| | - Shengxian Fan
- Department of General Surgery, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China
| | - Qian Wu
- Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P.R. China.
| | - Lei Li
- Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P.R. China.
| | - Zhan Zhang
- Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P.R. China.
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Haq S, Grondin JA, Khan WI. Tryptophan-derived serotonin-kynurenine balance in immune activation and intestinal inflammation. FASEB J 2021; 35:e21888. [PMID: 34473368 PMCID: PMC9292703 DOI: 10.1096/fj.202100702r] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 07/29/2021] [Accepted: 08/16/2021] [Indexed: 02/06/2023]
Abstract
Endogenous tryptophan metabolism pathways lead to the production of serotonin (5‐hydroxytryptamine; 5‐HT), kynurenine, and several downstream metabolites which are involved in a multitude of immunological functions in both health and disease states. Ingested tryptophan is largely shunted to the kynurenine pathway (95%) while only minor portions (1%–2%) are sequestered for 5‐HT production. Though often associated with the functioning of the central nervous system, significant production of 5‐HT, kynurenine and their downstream metabolites takes place within the gut. Accumulating evidence suggests that these metabolites have essential roles in regulating immune cell function, intestinal inflammation, as well as in altering the production and suppression of inflammatory cytokines. In addition, both 5‐HT and kynurenine have a considerable influence on gut microbiota suggesting that these metabolites impact host physiology both directly and indirectly via compositional changes. It is also now evident that complex interactions exist between the two pathways to maintain gut homeostasis. Alterations in 5‐HT and kynurenine are implicated in the pathogenesis of many gastrointestinal dysfunctions, including inflammatory bowel disease. Thus, these pathways present numerous potential therapeutic targets, manipulation of which may aid those suffering from gastrointestinal disorders. This review aims to update both the role of 5‐HT and kynurenine in immune regulation and intestinal inflammation, and analyze the current knowledge of the relationship and interactions between 5‐HT and kynurenine pathways.
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Affiliation(s)
- Sabah Haq
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Jensine A Grondin
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Waliul I Khan
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.,Laboratory Medicine, Hamilton Health Sciences, Hamilton, Ontario, Canada
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Marszalek-Grabska M, Walczak K, Gawel K, Wicha-Komsta K, Wnorowska S, Wnorowski A, Turski WA. Kynurenine emerges from the shadows – Current knowledge on its fate and function. Pharmacol Ther 2021; 225:107845. [DOI: 10.1016/j.pharmthera.2021.107845] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/29/2021] [Indexed: 12/12/2022]
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Zhao Y, Sun J, Li Y, Zhou X, Zhai W, Wu Y, Chen G, Gou S, Sui X, Zhao W, Qiu L, Yao Y, Sun Y, Chen C, Qi Y, Gao Y. Tryptophan 2,3-dioxygenase 2 controls M2 macrophages polarization to promote esophageal squamous cell carcinoma progression via AKT/GSK3 β/IL-8 signaling pathway. Acta Pharm Sin B 2021; 11:2835-2849. [PMID: 34589400 PMCID: PMC8463272 DOI: 10.1016/j.apsb.2021.03.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/29/2021] [Accepted: 02/10/2021] [Indexed: 12/27/2022] Open
Abstract
Tryptophan 2,3-dioxygnease 2 (TDO2) is specific for metabolizing tryptophan to kynurenine (KYN), which plays a critical role in mediating immune escape of cancer. Although accumulating evidence demonstrates that TDO2 overexpression is implicated in the development and progression of multiple cancers, its tumor-promoting role in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we observed that TDO2 was overexpressed in ESCC tissues and correlated significantly with lymph node metastasis, advanced clinical stage, and unfavorable prognosis. Functional experiments showed that TDO2 promoted tumor cell proliferation, migration, and colony formation, which could be prevented by inhibition of TDO2 and aryl hydrocarbon receptor (AHR). Further experimentation demonstrated that TDO2 could promote the tumor growth of KYSE150 tumor-bearing model, tumor burden of C57BL/6 mice with ESCC induced by 4-NQO, enhance the expression of phosphorylated AKT, with subsequent phosphorylation of GSK3β, and polarization of M2 macrophages by upregulating interleukin-8 (IL-8) to accelerate tumor progression in the tumor microenvironment (TME). Collectively, our results discovered that TDO2 could upregulate IL-8 through AKT/GSK3β to direct the polarization of M2 macrophages in ESCC, and suggested that TDO2 could represent as an attractive therapeutic target and prognostic marker to ESCC.
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Affiliation(s)
- Yumiao Zhao
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Jiaxin Sun
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yin Li
- Thoracic Surgery Department, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xiuman Zhou
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Wenjie Zhai
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yahong Wu
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Guanyu Chen
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
| | - Shanshan Gou
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Xinghua Sui
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
| | - Wenshan Zhao
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Lu Qiu
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yongjie Yao
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yixuan Sun
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Chunxia Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yuanming Qi
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
- Corresponding authors. Tel.: +86 371 67783235.
| | - Yanfeng Gao
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
- Corresponding authors. Tel.: +86 371 67783235.
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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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50
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Tang S, Wang J, Yu S. IDO in Colorectal Tumorigenesis: Involvement of Immune Tolerance and Significance in Prevention and Therapy. Cell Mol Gastroenterol Hepatol 2021; 12:1503-1504. [PMID: 34280382 PMCID: PMC8531978 DOI: 10.1016/j.jcmgh.2021.06.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 06/28/2021] [Indexed: 01/05/2023]
Affiliation(s)
| | | | - Siwang Yu
- Correspondence Address correspondence to: Siwang Yu, PhD, Peking University, School of Pharmaceutical Sciences, Department of Molecular and Cellular Pharmacology,38 Xueyuan Road, Haidian District, Beijing 100191, China. fax: +86-10-82802724
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