1
|
Failla M, Molaro MC, Schiano ME, Serafini M, Tiburtini GA, Gianquinto E, Scoccia R, Battisegola C, Rimoli MG, Chegaev K, Ercolano G, Lazzarato L, Spyrakis F, Sodano F. Opportunities and Challenges of Arginase Inhibitors in Cancer: A Medicinal Chemistry Perspective. J Med Chem 2024; 67:19988-20021. [PMID: 39558532 DOI: 10.1021/acs.jmedchem.4c01429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2024]
Abstract
The overexpression of two arginase (ARG) isoforms, ARG1 and ARG2, contributes to the onset of numerous disorders, including cardiovascular and immune-mediated diseases, as well as tumors. To elucidate the specific roles of ARG1 and ARG2 without interfering with their physiological functions, it is crucial to develop effective ARG inhibitors that target only one isoform, while maintaining low toxicity and an adequate pharmacokinetic profile. In this context, we present a comprehensive overview of the different generations of ARG inhibitors. Given the general lack of selectivity in most existing inhibitors, we analyzed the structural features and plasticity of the ARG1 and ARG2 binding sites to explore the potential for designing inhibitors with novel binding patterns. We also review ongoing preclinical and clinical studies on selected inhibitors, highlighting both progress and challenges in developing potent, selective ARG inhibitors. Furthermore, we discuss medicinal chemistry strategies that may accelerate the discovery of selective ARG inhibitors.
Collapse
Affiliation(s)
- Mariacristina Failla
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
| | | | | | - Marta Serafini
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
| | | | - Eleonora Gianquinto
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
| | - Riccardo Scoccia
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
| | - Chiara Battisegola
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
| | - Maria Grazia Rimoli
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
| | - Konstantin Chegaev
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
| | - Giuseppe Ercolano
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
| | - Loretta Lazzarato
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
| | - Francesca Spyrakis
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
| | - Federica Sodano
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
| |
Collapse
|
2
|
Xu B, Shi Y, Yuan C, Wang Z, Chen Q, Wang C, Chai J. Integrated gene-metabolite association network analysis reveals key metabolic pathways in gastric adenocarcinoma. Heliyon 2024; 10:e37156. [PMID: 39319160 PMCID: PMC11419903 DOI: 10.1016/j.heliyon.2024.e37156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 07/22/2024] [Accepted: 08/28/2024] [Indexed: 09/26/2024] Open
Abstract
Gastric adenocarcinoma is one of the most death cause cancers worldwide. Metabolomics is an effective approach for investigating the occurrence and progression of cancer and detecting prognostic biomarkers by studying the profiles of small bioactive molecules. To fully decipher the functional roles of the disrupted metabolites that modulate the cellular mechanism of gastric cancer, integrated gene-metabolite association network methods are critical to map the associations between metabolites and genes. In this study, we constructed a knowledge-based gene-metabolite association network of gastric cancer using the dysregulated metabolites and genes between gastric cancer patients and control group. The topological pathway analysis and gene-protein-metabolite-disease association analysis revealed four key gene-metabolite pathways which include eleven metabolites associated with modulated genes. The integrated gene-metabolite association network enables mechanistic investigation and provides a comprehensive overview regarding the investigation of molecular mechanisms of gastric cancer, which facilitates the in-depth understanding of metabolic biomarker roles in gastric cancer.
Collapse
Affiliation(s)
- Botao Xu
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, China
| | - Yuying Shi
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
- National Institute of Health Data Science of China, Shandong University, Jinan, 250000, China
- National Science Library (Chengdu), Chinese Academy of Sciences, Chengdu, 610299, China
| | - Chuang Yuan
- Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Zhe Wang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong, China
| | - Qitao Chen
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
- National Institute of Health Data Science of China, Shandong University, Jinan, 250000, China
| | - Cheng Wang
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
- National Institute of Health Data Science of China, Shandong University, Jinan, 250000, China
| | - Jie Chai
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, China
| |
Collapse
|
3
|
Marzęta-Assas P, Jacenik D, Zasłona Z. Pathophysiology of Arginases in Cancer and Efforts in Their Pharmacological Inhibition. Int J Mol Sci 2024; 25:9782. [PMID: 39337272 PMCID: PMC11431790 DOI: 10.3390/ijms25189782] [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: 08/05/2024] [Revised: 09/02/2024] [Accepted: 09/05/2024] [Indexed: 09/30/2024] Open
Abstract
Arginases are key enzymes that hydrolyze L-arginine to urea and L-ornithine in the urea cycle. The two arginase isoforms, arginase 1 (ARG1) and arginase 2 (ARG2), regulate the proliferation of cancer cells, migration, and apoptosis; affect immunosuppression; and promote the synthesis of polyamines, leading to the development of cancer. Arginases also compete with nitric oxide synthase (NOS) for L-arginine, and their participation has also been confirmed in cardiovascular diseases, stroke, and inflammation. Due to the fact that arginases play a crucial role in the development of various types of diseases, finding an appropriate candidate to inhibit the activity of these enzymes would be beneficial for the therapy of many human diseases. In this review, based on numerous experimental, preclinical, and clinical studies, we provide a comprehensive overview of the biological and physiological functions of ARG1 and ARG2, their molecular mechanisms of action, and affected metabolic pathways. We summarize the recent clinical trials' advances in targeting arginases and describe potential future drugs.
Collapse
Affiliation(s)
| | - Damian Jacenik
- Molecure S.A., 101 Żwirki i Wigury St., 02-089 Warsaw, Poland
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska St., 90-236 Lodz, Poland
| | | |
Collapse
|
4
|
Kasperski A, Heng HH. The Spiral Model of Evolution: Stable Life Forms of Organisms and Unstable Life Forms of Cancers. Int J Mol Sci 2024; 25:9163. [PMID: 39273111 PMCID: PMC11395208 DOI: 10.3390/ijms25179163] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 08/19/2024] [Accepted: 08/20/2024] [Indexed: 09/15/2024] Open
Abstract
If one must prioritize among the vast array of contributing factors to cancer evolution, environmental-stress-mediated chromosome instability (CIN) should easily surpass individual gene mutations. CIN leads to the emergence of genomically unstable life forms, enabling them to grow dominantly within the stable life form of the host. In contrast, stochastic gene mutations play a role in aiding the growth of the cancer population, with their importance depending on the initial emergence of the new system. Furthermore, many specific gene mutations among the many available can perform this function, decreasing the clinical value of any specific gene mutation. Since these unstable life forms can respond to treatment differently than stable ones, cancer often escapes from drug treatment by forming new systems, which leads to problems during the treatment for patients. To understand how diverse factors impact CIN-mediated macroevolution and genome integrity-ensured microevolution, the concept of two-phased cancer evolution is used to reconcile some major characteristics of cancer, such as bioenergetic, unicellular, and multicellular evolution. Specifically, the spiral of life function model is proposed, which integrates major historical evolutionary innovations and conservation with information management. Unlike normal organismal evolution in the microevolutionary phase, where a given species occupies a specific location within the spiral, cancer populations are highly heterogenous at multiple levels, including epigenetic levels. Individual cells occupy different levels and positions within the spiral, leading to supersystems of mixed cellular populations that exhibit both macro and microevolution. This analysis, utilizing karyotype to define the genetic networks of the cellular system and CIN to determine the instability of the system, as well as considering gene mutation and epigenetics as modifiers of the system for information amplification and usage, explores the high evolutionary potential of cancer. It provides a new, unified understanding of cancer as a supersystem, encouraging efforts to leverage the dynamics of CIN to develop improved treatment options. Moreover, it offers a historically contingent model for organismal evolution that reconciles the roles of both evolutionary innovation and conservation through macroevolution and microevolution, respectively.
Collapse
Affiliation(s)
- Andrzej Kasperski
- Department of Biotechnology, Laboratory of Bioinformatics and Control of Bioprocesses, Institute of Biological Sciences, University of Zielona Góra, Szafrana 1, 65-516 Zielona Góra, Poland
| | - Henry H Heng
- Center for Molecular Medicine and Genetics, Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| |
Collapse
|
5
|
Bi B, Fu X, Jian X, Zhang Y, Jiang Y, Zhou W, Zhao H. Assessment of the potential risks in SD rats gavaged with genetically modified yeast containing the cp4-epsps gene. Front Vet Sci 2024; 11:1411520. [PMID: 39170628 PMCID: PMC11335726 DOI: 10.3389/fvets.2024.1411520] [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: 04/03/2024] [Accepted: 06/21/2024] [Indexed: 08/23/2024] Open
Abstract
Introduction Despite the absence of definitive evidence indicating that the cp4-epsps gene and its resultant recombinant proteins have significant harmful effects on either human or animal health, the safety assessment of genetically modified (GM) crops expressing the CP4-EPSPS proteins has been controversial. This study endeavor was aimed at evaluating the potential risks posed by the CP4-EPSPS protein in transgenic crops, thereby contributing to the advancement of risk assessment methodologies in the context of genetically engineered crops. Methods To ascertain the appropriate daily dosages for oral gavage administration, the expression levels of the CP4-EPSPS protein in a recombinant yeast were quantified. Subsequently, physiological and biochemical analysis, metabolomics, and metagenomic analysis were conducted based on a 90-day Sprague-Dawley (SD) rats feeding experiment, respectively, thereby enhancing the depth and precision of our risk assessment framework. Results The results from the physiological and biochemical analysis, organ pathological, blood metabolism, gut microbiota, and correlation analysis of metabolites and gut microbiota revealed several biomarkers for further risk assessment. These biomarkers include clinical biochemical indexes such as total bilirubin (TBIL), direct bilirubin (DBIL), creatine kinase (CK), and lactate dehydrogenase (LDH); metabolites like Methionine, 2-Oxovaleric acid, and LysoPC (16:0); and gut microbiota including Blautia wexlerae, Holdemanella biformis, Dorea sp. CAG 317, Coriobacteriaceae and Erysipelotrichaceae. Conclusion In conclusion, the risk can be significantly reduced by directly consuming inactivated recombinant CP4-EPSPS. Therefore, in everyday life, the risk associated with consuming GM foods containing recombinant CP4-EPSPS is substantially reduced after heat treatment.
Collapse
Affiliation(s)
- Bo Bi
- Key Laboratory for Biobased Materials and Energy of Ministry of Education, Research Center of Biomass 3D Printing Materials, College of Materials and Energy, South China Agricultural University, Guangzhou, China
- College of Food Science, South China Agricultural University, Guangzhou, China
| | - Xuewei Fu
- Key Laboratory for Biobased Materials and Energy of Ministry of Education, Research Center of Biomass 3D Printing Materials, College of Materials and Energy, South China Agricultural University, Guangzhou, China
| | - Xuewen Jian
- Key Laboratory for Biobased Materials and Energy of Ministry of Education, Research Center of Biomass 3D Printing Materials, College of Materials and Energy, South China Agricultural University, Guangzhou, China
| | - Yu Zhang
- Key Laboratory for Biobased Materials and Energy of Ministry of Education, Research Center of Biomass 3D Printing Materials, College of Materials and Energy, South China Agricultural University, Guangzhou, China
| | - Yizhi Jiang
- Guangzhou Zhixin High School, Guangzhou, China
| | - Wuyi Zhou
- Key Laboratory for Biobased Materials and Energy of Ministry of Education, Research Center of Biomass 3D Printing Materials, College of Materials and Energy, South China Agricultural University, Guangzhou, China
| | - Hui Zhao
- Key Laboratory for Biobased Materials and Energy of Ministry of Education, Research Center of Biomass 3D Printing Materials, College of Materials and Energy, South China Agricultural University, Guangzhou, China
| |
Collapse
|
6
|
da Silva Costa SM, Ito MT, da Cruz PRS, De Souza BB, Rios VM, Bertozzo VDHE, Camargo ACL, Viturino MGM, Lanaro C, de Albuquerque DM, do Canto AM, Saad STO, Ospina-Prieto S, Ozelo MC, Costa FF, de Melo MB. The molecular mechanism responsible for HbSC retinopathy may depend on the action of the angiogenesis-related genes ROBO1 and SLC38A5. Exp Biol Med (Maywood) 2024; 249:10070. [PMID: 39114443 PMCID: PMC11303203 DOI: 10.3389/ebm.2024.10070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 07/08/2024] [Indexed: 08/10/2024] Open
Abstract
HbSC disease, a less severe form of sickle cell disease, affects the retina more frequently and patients have higher rates of proliferative retinopathy that can progress to vision loss. This study aimed to identify differences in the expression of endothelial cell-derived molecules associated with the pathophysiology of proliferative sickle cell retinopathy (PSCR). RNAseq was used to compare the gene expression profile of circulating endothelial colony-forming cells from patients with SC hemoglobinopathy and proliferative retinopathy (n = 5), versus SC patients without retinopathy (n = 3). Real-time polymerase chain reaction (qRT-PCR) was used to validate the RNAseq results. A total of 134 differentially expressed genes (DEGs) were found. DEGs were mainly associated with vasodilatation, type I interferon signaling, innate immunity and angiogenesis. Among the DEGs identified, we highlight the most up-regulated genes ROBO1 (log2FoldChange = 4.32, FDR = 1.35E-11) and SLC38A5 (log2FoldChange = 3.36 FDR = 1.59E-07). ROBO1, an axon-guided receptor, promotes endothelial cell migration and contributes to the development of retinal angiogenesis and pathological ocular neovascularization. Endothelial SLC38A5, an amino acid (AA) transporter, regulates developmental and pathological retinal angiogenesis by controlling the uptake of AA nutrient, which may serve as metabolic fuel for the proliferation of endothelial cells (ECs) and consequent promotion of angiogenesis. Our data provide an important step towards elucidating the molecular pathophysiology of PSCR that may explain the differences in ocular manifestations between individuals with hemoglobinopathies and afford insights for new alternative strategies to inhibit pathological angiogenesis.
Collapse
Affiliation(s)
| | - Mirta Tomie Ito
- Center for Molecular Biology and Genetic Engineering, State University of Campinas—UNICAMP, Campinas, Brazil
| | | | - Bruno Batista De Souza
- Center for Molecular Biology and Genetic Engineering, State University of Campinas—UNICAMP, Campinas, Brazil
| | - Vinicius Mandolesi Rios
- Center for Molecular Biology and Genetic Engineering, State University of Campinas—UNICAMP, Campinas, Brazil
| | - Victor de Haidar e Bertozzo
- Center for Molecular Biology and Genetic Engineering, State University of Campinas—UNICAMP, Campinas, Brazil
| | - Ana Carolina Lima Camargo
- Center for Molecular Biology and Genetic Engineering, State University of Campinas—UNICAMP, Campinas, Brazil
| | | | - Carolina Lanaro
- Centro de Hematologia e Hemoterapia, Universidade Estadual de Campinas—UNICAMP, Campinas, Brazil
| | | | - Amanda Morato do Canto
- Departamento de Medicina Translacional, Faculdade de Ciências Médicas, Universidade Estadual de Campinas—UNICAMP, Campinas, Brazil
| | | | - Stephanie Ospina-Prieto
- Centro de Hematologia e Hemoterapia, Universidade Estadual de Campinas—UNICAMP, Campinas, Brazil
| | - Margareth Castro Ozelo
- Centro de Hematologia e Hemoterapia, Universidade Estadual de Campinas—UNICAMP, Campinas, Brazil
| | - Fernando Ferreira Costa
- Centro de Hematologia e Hemoterapia, Universidade Estadual de Campinas—UNICAMP, Campinas, Brazil
| | - Mônica Barbosa de Melo
- Center for Molecular Biology and Genetic Engineering, State University of Campinas—UNICAMP, Campinas, Brazil
| |
Collapse
|
7
|
Wang Y, An R, Yu H, Dai Y, Lou L, Quan S, Chen R, Ding Y, Zhao H, Wu X, Liu Z, Wang Q, Gao Y, Xie X, Zhang J. Largescale multicenter study of a serum metabolite biomarker panel for the diagnosis of breast cancer. iScience 2024; 27:110345. [PMID: 39055906 PMCID: PMC11269948 DOI: 10.1016/j.isci.2024.110345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 05/23/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
Breast cancer (BC) is currently the most prevalent malignancy worldwide, and finding effective non-invasive biomarkers for routine clinical detection of BC remains a significant challenge. Here, we performed non-targeted and targeted metabolomics analysis on the screening, training and validation cohorts of serum samples from 1,947 participants. A metabolite biomarker model including glutamate, erythronate, docosahexaenoate, propionylcarnitine, and patient's age was established for detecting BC. This model demonstrated better diagnostic performance than carbohydrate antigen 15-3 (CA15-3) and carcinoembryonic antigen (CEA) alone in discriminating BC from healthy controls both in the training and validation cohorts [area under the curve (AUC), 0.954; sensitivity, 87.1% and specificity, 93.5% for the training cohort and 0.834, 68.3%, and 85.2%, respectively, for the validation cohort 1]. This study has established a noninvasive approach for the detection of BC, which shows potential as a suitable supplement to the clinical screening methods currently employed for BC.
Collapse
Affiliation(s)
- Yanzhong Wang
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
| | - Rui An
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
| | - Haitao Yu
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
| | - Yuehong Dai
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
| | - Luping Lou
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
| | - Sheng Quan
- Hangzhou Calibra Diagnostics Co., Ltd. (A Subsidiary of DIAN Diagnostics), 329 Jinpeng Street, Xihu Industrial Park, Hangzhou, Zhejiang, People’s Republic of China
| | - Rongchang Chen
- Hangzhou Calibra Diagnostics Co., Ltd. (A Subsidiary of DIAN Diagnostics), 329 Jinpeng Street, Xihu Industrial Park, Hangzhou, Zhejiang, People’s Republic of China
| | - Yanjun Ding
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
| | - Hongcan Zhao
- Department of Clinical Laboratory, Affiliated Hangzhou First People’s Hospital, Westlake University School of Medicine, 261 Huansha Road, Hangzhou, Zhejiang, People’s Republic of China
| | - Xuanlan Wu
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital Xiasha Campus, Zhejiang University School of Medicine, 368 Xiasha Road, Hangzhou, Zhejiang, People’s Republic of China
| | - Zhen Liu
- Department of Clinical Laboratory, Ningbo Medical Centre Lihuili Hospital, Ningbo University, 1111 Jiangnan Street, Ningbo, Zhejiang, People’s Republic of China
| | - Qinchuan Wang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
| | - Yuzhen Gao
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
| | - Xinyou Xie
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
| | - Jun Zhang
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, 3 East Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China
| |
Collapse
|
8
|
Hao S, Shen L, Liu P, Yong Q, Wang Y, Zheng X. Development of a prognostic model for muscle-invasive bladder cancer using glutamine metabolism. Comput Biol Med 2024; 171:108223. [PMID: 38430744 DOI: 10.1016/j.compbiomed.2024.108223] [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: 11/07/2023] [Revised: 01/31/2024] [Accepted: 02/25/2024] [Indexed: 03/05/2024]
Abstract
BACKGROUND Muscle-invasive bladder cancer (MIBC) is distinguished by its pronounced invasiveness and unfavorable prognosis. Immunotherapy and targeted therapy have emerged as key treatment options for various types of cancer. Altered metabolism is a defining characteristic of cancer cells, and there is mounting evidence suggesting the important role of glutamine metabolism (GM) in tumor metabolism. Nevertheless, the relationship between GM and clinical outcomes, immune microenvironment, and immunotherapy in MIBC remains unknown. METHODS This study employed Mendelian randomization to explore the causal relationship between blood metabolites and bladder tumors. We systematically evaluated 373 glutamine metabolism-related genes and identified prognostic-related genes, leading to the construction of a glutamine-associated prognostic model. Further analysis confirmed the correlation between high and low-risk groups with the tumor microenvironment, immune cell infiltration, and tumor mutation burden. Subsequently, we assessed the relationship between the risk score and the sensitivity to various immunotherapies and anticancer drugs. RESULTS We identified 14 blood metabolites at the molecular level that have a causal relationship with bladder tumors. At the gene level, the study discussed differentially expressed GM genes in MIBC. First, we established a risk model predicting overall survival (OS) based on GM genes, confirming its reliable predictive ability in MIBC patients and validated it in a GEO cohort. Additionally, a reliable column line chart was created. Secondly, two distinct molecular subtypes were identified, and the associations between different risk groups and tumor microenvironment and immune infiltration were observed. In addition, the predicted risk values correlated with responses to a broad range of pharmaceutical agents. CONCLUSION In summary, we confirmed the causal relationship between blood metabolites and bladder tumors. Furthermore, a risk scoring model related to glutamine metabolism consisting of 9 genes was developed. This model could potentially serve as a useful tool for predicting prognosis and guiding the treatment of MIBC patients.
Collapse
Affiliation(s)
- Sida Hao
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China; Department of Urology, Zhejiang Integrated Traditional Chinese and Western Medicine Hospital, Hangzhou, 310003, Zhejiang, China.
| | - Lin Shen
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China.
| | - Pengju Liu
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China.
| | - Qin Yong
- Department of Urology, Zhejiang Integrated Traditional Chinese and Western Medicine Hospital, Hangzhou, 310003, Zhejiang, China.
| | - Yeqiang Wang
- Department of Urology, Zhejiang Integrated Traditional Chinese and Western Medicine Hospital, Hangzhou, 310003, Zhejiang, China.
| | - Xiangyi Zheng
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China.
| |
Collapse
|
9
|
Benabdelkamel H, Jaber MA, Akkour K, AlMalki RH, Alfadda AA, Masood A, Joy SS, Alhalal H, Alwehaibi MA, Arafah M, Alshehri E, Abdel Rahman AM. Metabolomic Profiling of Blood Plasma in Females with Hyperplasia and Endometrial Cancer. Metabolites 2024; 14:109. [PMID: 38393001 PMCID: PMC10890097 DOI: 10.3390/metabo14020109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 01/27/2024] [Accepted: 01/30/2024] [Indexed: 02/25/2024] Open
Abstract
Uterine cancer is the most prevalent gynecologic malignancy in women worldwide. Endometrial cancer (EC) has an 81% five-year survival rate, depending on disease stage and time of diagnosis. While endometrial cancer is largely treatable when detected early, no established screening techniques are available in clinical practice. As a result, one of the most significant issues in the medical field is the development of novel ways for early cancer identification, which could boost treatment success rates. Liquid chromatography-high-resolution mass spectrometry (LC-HRMS)-based metabolomics was employed to explore the metabolomic markers and pathways unique to this cancer type and link them to the benign endometrial hyperplasia that may progress to cancer in 5% to 25% of patients. The study involved 59 postmenopausal participants, 20 with EC type 1, 20 with benign hyperplasia, and 19 healthy participants. Metabolite distribution changes were analyzed, and 338 of these features were dysregulated and significant. The first two main components, PC1 and PC2, were responsible for 11.5% and 12.2% of the total metabolites, respectively. Compared with the control group (CO), EC samples had 203 differentially expressed metabolites (180 upregulated and 23 downregulated); in hyperplasia (HP), 157 metabolites were dysregulated (127 upregulated and 30 downregulated) compared to the CO group while 21 metabolites exhibited differential regulation (16 upregulated and 5 downregulated) in EC plasma samples compared to the HP group. Hyperplasia samples exhibited similar metabolic changes to those reported in cancer, except for alterations in triglyceride levels, 7a,12 b-dihydroxy-5b-Cholan-24-oic acid, and Hept-2-enedioyl carnitine levels. The metabolites N-heptanoyl glycine and -(Methylthio)-2,3-isopentyl phosphate and formimino glutamic acid can be specific markers for hyperplasia conditions and dimethyl phosphatidyl ethanolamine and 8-isoprostaglandin E2 can be specific markers for EC conditions. Metabolic activities rely on mitochondrial oxidative phosphorylation for energy generation. The changes in metabolites identified in our study indicate that endometrial cancer cells adopt alternative strategies to increase energy production to meet the energy demand, thereby supporting proliferation.
Collapse
Affiliation(s)
- Hicham Benabdelkamel
- Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | - Malak A Jaber
- Pharmaceutical Medicinal Chemistry & Pharmacognosy, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman 1196, Jordan
| | - Khalid Akkour
- Obstetrics and Gynecology Department, College of Medicine, King Saud University Medical City, King Saud University, Riyadh 11461, Saudi Arabia
| | - Reem H AlMalki
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11461, Saudi Arabia
| | - Assim A Alfadda
- Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
- Department of Medicine, College of Medicine, King Saud University Medical City, King Saud University, Riyadh 11461, Saudi Arabia
| | - Afshan Masood
- Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | - Salini Scaria Joy
- Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | - Hani Alhalal
- Obstetrics and Gynecology Department, College of Medicine, King Saud University Medical City, King Saud University, Riyadh 11461, Saudi Arabia
| | - Moudi A Alwehaibi
- Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | - Maria Arafah
- Department of Pathology, College of Medicine, King Saud University Medical City, King Saud University, Riyadh 11461, Saudi Arabia
| | - Eman Alshehri
- Obstetrics and Gynecology Department, College of Medicine, King Saud University Medical City, King Saud University, Riyadh 11461, Saudi Arabia
| | - Anas M Abdel Rahman
- Metabolomics Section, Department of Clinical Genomics, Center for Genome Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, Saudi Arabia
| |
Collapse
|
10
|
Taurino G, Chiu M, Bianchi MG, Griffini E, Bussolati O. The SLC38A5/SNAT5 amino acid transporter: from pathophysiology to pro-cancer roles in the tumor microenvironment. Am J Physiol Cell Physiol 2023; 325:C550-C562. [PMID: 37458433 DOI: 10.1152/ajpcell.00169.2023] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/11/2023] [Accepted: 07/11/2023] [Indexed: 08/09/2023]
Abstract
SLC38A5/SNAT5 is a system N transporter that can mediate net inward or outward transmembrane fluxes of neutral amino acids coupled with Na+ (symport) and H+ (antiport). Its preferential substrates are not only amino acids with side chains containing amide (glutamine and asparagine) or imidazole (histidine) groups, but also serine, glycine, and alanine are transported by the carrier. Expressed in the pancreas, intestinal tract, brain, liver, bone marrow, and placenta, it is regulated at mRNA and protein levels by mTORC1 and WNT/β-catenin pathways, and it is sensitive to pH, nutritional stress, inflammation, and hypoxia. SNAT5 expression has been found to be altered in pathological conditions such as chronic inflammatory diseases, gestational complications, chronic metabolic acidosis, and malnutrition. Growing experimental evidence shows that SNAT5 is overexpressed in several types of cancer cells. Moreover, recently published results indicate that SNAT5 expression in stromal cells can support the metabolic exchanges occurring in the tumor microenvironment of asparagine-auxotroph tumors. We review the functional role of the SNAT5 transporter in pathophysiology and propose that, due to its peculiar operational and regulatory features, SNAT5 may play important pro-cancer roles when expressed either in neoplastic or in stromal cells of glutamine-auxotroph tumors.NEW & NOTEWORTHY The transporter SLC38A5/SNAT5 provides net influx or efflux of glutamine, asparagine, and serine. These amino acids are of particular metabolic relevance in several conditions. Changes in transporter expression or activity have been described in selected types of human cancers, where SNAT5 can mediate amino acid exchanges between tumor and stromal cells, thus providing a potential therapeutic target. This is the first review that recapitulates the characteristics and roles of the transporter in physiology and pathology.
Collapse
Affiliation(s)
- Giuseppe Taurino
- Laboratory of General Pathology, Department of Medicine and Surgery, University of Parma, Parma, Italy
- MRH-Microbiome Research Hub, University of Parma, Parma, Italy
| | - Martina Chiu
- Laboratory of General Pathology, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Massimiliano G Bianchi
- Laboratory of General Pathology, Department of Medicine and Surgery, University of Parma, Parma, Italy
- MRH-Microbiome Research Hub, University of Parma, Parma, Italy
| | - Erika Griffini
- Laboratory of General Pathology, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Ovidio Bussolati
- Laboratory of General Pathology, Department of Medicine and Surgery, University of Parma, Parma, Italy
- MRH-Microbiome Research Hub, University of Parma, Parma, Italy
| |
Collapse
|
11
|
Yi Y, Wang J, Liang C, Ren C, Lian X, Han C, Sun W. LC-MS-based serum metabolomics analysis for the screening and monitoring of colorectal cancer. Front Oncol 2023; 13:1173424. [PMID: 37448516 PMCID: PMC10338013 DOI: 10.3389/fonc.2023.1173424] [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: 02/24/2023] [Accepted: 06/14/2023] [Indexed: 07/15/2023] Open
Abstract
Background Colorectal Cancer (CRC) is a prevalent digestive system tumour with significant mortality and recurrence rates. Serum metabolomics, with its high sensitivity and high throughput, has shown potential as a tool to discover biomarkers for clinical screening and monitoring of the CRC patients. Methods Serum metabolites of 61 sex and age-matched healthy controls and 62 CRC patients (before and after surgical intervention) were analyzed using a ultra-performance liquid chromatography-high resolution mass spectrometer (UPLC-MS). Statistical methods and pathway enrichment analysis were used to identify potential biomarkers and altered metabolic pathways. Results Our analysis revealed a clear distinction in the serum metabolic profile between CRC patients and healthy controls (HCs). Pathway analysis indicated a significant association with arginine biosynthesis, pyrimidine metabolism, pantothenate, and CoA biosynthesis. Univariate and multivariate statistical analysis showed that 9 metabolites had significant diagnostic value for CRC, among them, Guanosine with Area Under the Curve (AUC) values of 0.951 for the training group and0.998 for the validation group. Furthermore, analysis of four specific metabolites (N-Phenylacetylasparticacid, Tyrosyl-Gamma-glutamate, Tyr-Ser and Sphingosine) in serum samples of CRC patients before and after surgery indicated a return to healthy levels after an intervention. Conclusion Our results suggest that serum metabolomics may be a valuable tool for the screening and monitoring of CRC patients.
Collapse
Affiliation(s)
- Yanan Yi
- Department of Laboratory Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Jianjian Wang
- Department of Laboratory Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Chengtong Liang
- Department of Laboratory Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Chuanli Ren
- Department of Laboratory Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Xu Lian
- Department of Laboratory Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Chongxu Han
- Department of Laboratory Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Wei Sun
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| |
Collapse
|
12
|
Fasoulakis Z, Koutras A, Ntounis T, Prokopakis I, Perros P, Chionis A, Sapantzoglou I, Katrachouras A, Konis K, Samara AA, Valsamaki A, Palios VC, Symeonidis P, Nikolettos K, Pagkalos A, Sotiriou S, Theodora M, Antsaklis P, Daskalakis G, Kontomanolis EN. Ovarian Cancer and Glutamine Metabolism. Int J Mol Sci 2023; 24:5041. [PMID: 36902470 PMCID: PMC10003179 DOI: 10.3390/ijms24055041] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 02/24/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Cancer cells are known to have a distinct metabolic profile and to exhibit significant changes in a variety of metabolic mechanisms compared to normal cells, particularly glycolysis and glutaminolysis, in order to cover their increased energy requirements. There is mounting evidence that there is a link between glutamine metabolism and the proliferation of cancer cells, demonstrating that glutamine metabolism is a vital mechanism for all cellular processes, including the development of cancer. Detailed knowledge regarding its degree of engagement in numerous biological processes across distinct cancer types is still lacking, despite the fact that such knowledge is necessary for comprehending the differentiating characteristics of many forms of cancer. This review aims to examine data on glutamine metabolism and ovarian cancer and identify possible therapeutic targets for ovarian cancer treatment.
Collapse
Affiliation(s)
- Zacharias Fasoulakis
- 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece
| | - Antonios Koutras
- 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece
| | - Thomas Ntounis
- 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece
| | - Ioannis Prokopakis
- 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece
| | - Paraskevas Perros
- 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece
| | - Athanasios Chionis
- Department of Obstetrics and Gynecology, Laiko General Hospital of Athens, Agiou Thoma 17, 11527 Athens, Greece
| | - Ioakeim Sapantzoglou
- 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece
| | - Alexandros Katrachouras
- Department of Obstetrics and Gynecology, University General Hospital of Ioannina, University of Ioannina, Stavrou Niarchou Str., 45500 Ioannina, Greece
| | - Kyriakos Konis
- Department of Obstetrics and Gynecology, General Hospital of Arta, Lofos Peranthis, 47100 Arta, Greece
| | - Athina A. Samara
- Department of Embryology, University Hospital of Larissa, Mezourlo, 41110 Larissa, Greece
| | - Asimina Valsamaki
- Department of Internal Medicine, General Hospital of Larisa, Tsakalof 1, 41221 Larisa, Greece
| | | | - Panagiotis Symeonidis
- Department of Obstetrics and Gynecology, University General Hospital of Alexandroupolis, 6th klm Alexandroupolis-Makris, Dragana Alexandroupolis, 68100 Alexandroupolis, Greece
| | - Konstantinos Nikolettos
- Department of Obstetrics and Gynecology, Democritus University of Thrace, 6th km Alexandroupolis-Makris, 68100 Alexandroupolis, Greece
| | - Athanasios Pagkalos
- Department of Obstetrics and Gynecology, General Hospital of Xanthi, Neapoli, 67100 Xanthi, Greece
| | - Sotirios Sotiriou
- Department of Embryology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41110 Larissa, Greece
| | - Marianna Theodora
- 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece
| | - Panos Antsaklis
- 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece
| | - Georgios Daskalakis
- 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece
| | - Emmanuel N. Kontomanolis
- Department of Obstetrics and Gynecology, Democritus University of Thrace, 6th km Alexandroupolis-Makris, 68100 Alexandroupolis, Greece
| |
Collapse
|
13
|
Cell Metabolomics Reveals the Potential Mechanism of Aloe Emodin and Emodin Inhibiting Breast Cancer Metastasis. Int J Mol Sci 2022; 23:ijms232213738. [PMID: 36430215 PMCID: PMC9694700 DOI: 10.3390/ijms232213738] [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: 10/09/2022] [Revised: 11/02/2022] [Accepted: 11/04/2022] [Indexed: 11/11/2022] Open
Abstract
Metastasis is one of the main obstacles for the treatment and prognosis of breast cancer. In this study, the effects and possible mechanisms of aloe emodin (AE) and emodin (EMD) for inhibiting breast cancer metastasis were investigated via cell metabolomics. First, a co-culture model of MCF-7 and HUVEC cells was established and compared with a traditional single culture of MCF-7 cells. The results showed that HUVEC cells could promote the development of cancer cells to a malignant phenotype. Moreover, AE and EMD could inhibit adhesion, invasion, and angiogenesis and induce anoikis of MCF-7 cells in co-culture model. Then, the potential mechanisms behind AE and EMD inhibition of MCF-7 cell metastasis were explored using a metabolomics method based on UPLC-Q-TOF/MS multivariate statistical analysis. Consequently, 27 and 13 biomarkers were identified in AE and EMD groups, respectively, including polyamine metabolism, methionine cycle, TCA cycle, glutathione metabolism, purine metabolism, and aspartate synthesis. The typical metabolites were quantitatively analyzed, and the results showed that the inhibitory effect of AE was significantly better than EMD. All results confirmed that AE and EMD could inhibit metastasis of breast cancer cells through different pathways. Our study provides an overall view of the underlying mechanisms of AE and EMD against breast cancer metastasis.
Collapse
|
14
|
An R, Yu H, Wang Y, Lu J, Gao Y, Xie X, Zhang J. Integrative analysis of plasma metabolomics and proteomics reveals the metabolic landscape of breast cancer. Cancer Metab 2022; 10:13. [PMID: 35978348 PMCID: PMC9382832 DOI: 10.1186/s40170-022-00289-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 08/03/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Breast cancer (BC) is the most commonly diagnosed cancer. Currently, mammography and breast ultrasonography are the main clinical screening methods for BC. Our study aimed to reveal the specific metabolic profiles of BC patients and explore the specific metabolic signatures in human plasma for BC diagnosis. METHODS This study enrolled 216 participants, including BC patients, benign patients, and healthy controls (HC) and formed two cohorts, one training cohort and one testing cohort. Plasma samples were collected from each participant and subjected to perform nontargeted metabolomics and proteomics. The metabolic signatures for BC diagnosis were identified through machine learning. RESULTS Metabolomics analysis revealed that BC patients showed a significant change of metabolic profiles compared to HC individuals. The alanine, aspartate and glutamate pathways, glutamine and glutamate metabolic pathways, and arginine biosynthesis pathways were the critical biological metabolic pathways in BC. Proteomics identified 29 upregulated and 2 downregulated proteins in BC. Our integrative analysis found that aspartate aminotransferase (GOT1), L-lactate dehydrogenase B chain (LDHB), glutathione synthetase (GSS), and glutathione peroxidase 3 (GPX3) were closely involved in these metabolic pathways. Support vector machine (SVM) demonstrated a predictive model with 47 metabolites, and this model achieved a high accuracy in BC prediction (AUC = 1). Besides, this panel of metabolites also showed a fairly high predictive power in the testing cohort between BC vs HC (AUC = 0.794), and benign vs HC (AUC = 0.879). CONCLUSIONS This study uncovered specific changes in the metabolic and proteomic profiling of breast cancer patients and identified a panel of 47 plasma metabolites, including sphingomyelins, glutamate, and cysteine could be potential diagnostic biomarkers for breast cancer.
Collapse
Affiliation(s)
- Rui An
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, 310016, People's Republic of China.,Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, 3 East Qingchun Road, Hangzhou, Zhejiang, 310016, People's Republic of China
| | - Haitao Yu
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, 310016, People's Republic of China.,Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, 3 East Qingchun Road, Hangzhou, Zhejiang, 310016, People's Republic of China
| | - Yanzhong Wang
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, 310016, People's Republic of China.,Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, 3 East Qingchun Road, Hangzhou, Zhejiang, 310016, People's Republic of China
| | - Jie Lu
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, 310016, People's Republic of China.,Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, 3 East Qingchun Road, Hangzhou, Zhejiang, 310016, People's Republic of China
| | - Yuzhen Gao
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, 310016, People's Republic of China.,Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, 3 East Qingchun Road, Hangzhou, Zhejiang, 310016, People's Republic of China
| | - Xinyou Xie
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, 310016, People's Republic of China.,Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, 3 East Qingchun Road, Hangzhou, Zhejiang, 310016, People's Republic of China
| | - Jun Zhang
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, 310016, People's Republic of China. .,Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, 3 East Qingchun Road, Hangzhou, Zhejiang, 310016, People's Republic of China.
| |
Collapse
|
15
|
13C Natural Isotope Abundance in Urothelium as a New Marker in the Follow-Up of Patients with Bladder Cancer. Cancers (Basel) 2022; 14:cancers14102423. [PMID: 35626027 PMCID: PMC9140021 DOI: 10.3390/cancers14102423] [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: 04/13/2022] [Revised: 05/08/2022] [Accepted: 05/10/2022] [Indexed: 02/01/2023] Open
Abstract
Bladder cancer (BC) is the most common urological malignancy and has a high incidence of recurrence. BC cells alter their nutrient uptake and metabolic pathways in order to continue the production of sufficient levels of ATP and metabolic intermediates for proliferation and survival. Changes in metabolic pathways regarding the rate of the enzymatic reaction and transport lead to differences in the content of natural isotopes (13C, 15N, 34S) between normal and cancerous tissues. The assessment of the stable isotopes of carbon, nitrogen, and sulfur in normal urothelium and bladder cancer samples was performed using Isotope Ratio Mass Spectrometry (IRMS). The natural abundance of 15N and 13C was decreased in bladder cancer samples when compared to normal urothelium. No significant correlation was observed in BC specimens depending on the tumor grade and stage. Samples derived from bladder tumors and normal urothelium had a different pattern of 15N and 13C isotope abundance. Decreased 13C natural isotopes in the normal urothelium of BC patients were significantly associated with a shorter DFS. Our results suggest that isotopic analysis of normal urothelium of BC patients can be used to predict bladder cancer recurrence.
Collapse
|
16
|
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.
Collapse
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
| |
Collapse
|
17
|
Jyotsana N, Ta KT, DelGiorno KE. The Role of Cystine/Glutamate Antiporter SLC7A11/xCT in the Pathophysiology of Cancer. Front Oncol 2022; 12:858462. [PMID: 35280777 PMCID: PMC8904967 DOI: 10.3389/fonc.2022.858462] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 02/04/2022] [Indexed: 12/12/2022] Open
Abstract
SLC7A11/xCT is an antiporter that mediates the uptake of extracellular cystine in exchange for glutamate. Cystine is reduced to cysteine, which is a rate-limiting precursor in glutathione synthesis; a process that protects cells from oxidative stress and is, therefore, critical to cell growth, proliferation, and metabolism. SLC7A11 is expressed in different tissues and plays diverse functional roles in the pathophysiology of various diseases, including cancer, by regulating the processes of redox homeostasis, metabolic flexibility/nutrient dependency, immune system function, and ferroptosis. SLC7A11 expression is associated with poor prognosis and drug resistance in cancer and, therefore, represents an important therapeutic target. In this review, we discuss the molecular functions of SLC7A11 in normal versus diseased tissues, with a special focus on how it regulates gastrointestinal cancers. Further, we summarize current therapeutic strategies targeting SLC7A11 as well as novel avenues for treatment.
Collapse
Affiliation(s)
- Nidhi Jyotsana
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, United States
| | - Kenny T. Ta
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, United States
| | - Kathleen E. DelGiorno
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, United States
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, United States
- Vanderbilt Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, TN, United States
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, United States
| |
Collapse
|
18
|
Çakıcı ÖU, Dinçer S. The effect of amino acids on the bladder cycle: a concise review. Amino Acids 2021; 54:13-31. [PMID: 34853916 DOI: 10.1007/s00726-021-03113-5] [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: 06/17/2021] [Accepted: 11/25/2021] [Indexed: 11/26/2022]
Abstract
The human bladder maintains a cycle of filling, storing, and micturating throughout an individual's lifespan. The cycle relies on the ability of the bladder to expand without increasing the intravesical pressure, which is only possible with the controlled relaxation of well-complaint muscles and the congruously organized construction of the bladder wall. A competent bladder outlet, which functions in a synchronous fashion with the bladder, is also necessary for this cycle to be completed successfully without deterioration. In this paper, we aimed to review the contemporary physiological findings on bladder physiology and examine the effects of amino acids on clinical conditions affecting the bladder, with special emphasis on the available therapeutic evidence and possible future roles of the amino acids in the treatment of the bladder-related disorders.
Collapse
Affiliation(s)
- Özer Ural Çakıcı
- Attending Urologist, Private Practice, Ankara, Turkey.
- PhD Candidate in Physiology, Department of Physiology, Gazi University, Ankara, Turkey.
| | - Sibel Dinçer
- Professor in Physiology, Department of Physiology, Gazi University, Ankara, Turkey
| |
Collapse
|
19
|
Pudakalakatti S, Audia A, Mukhopadhyay A, Enriquez JS, Bourgeois D, Tayob N, Zacharias NM, Millward SW, Carson D, Farach-Carson MC, Lang FF, Heimberger AB, Bhat KP, Bhattacharya PK. NMR Spectroscopy-Based Metabolomics of Platelets to Analyze Brain Tumors. REPORTS 2021; 4. [PMID: 35937580 PMCID: PMC9352435 DOI: 10.3390/reports4040032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
“Tumor-educated platelets” have recently generated substantial interest for the diagnosis of cancer. We hypothesized that tumor educated platelets from patients with brain tumors will reflect altered metabolism compared to platelets from healthy volunteers. Here, in a pilot study, we have employed nuclear magnetic resonance (NMR) spectroscopy in platelets from brain tumor patients to demonstrate altered metabolism compared to the platelets obtained from healthy volunteers.
Collapse
Affiliation(s)
- Shivanand Pudakalakatti
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Alessandra Audia
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Center Center, Houston, TX 77030, USA
| | - Anirudh Mukhopadhyay
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - José S. Enriquez
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77054, USA
| | | | - Nabihah Tayob
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Niki M. Zacharias
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77054, USA
- Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Steven W. Millward
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77054, USA
| | - Daniel Carson
- Department of BioSciences, Rice University, Houston, TX 77005, USA
| | - Mary C. Farach-Carson
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77054, USA
- Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center, Houston, TX 77054, USA
| | - Frederick F. Lang
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77054, USA
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Amy B. Heimberger
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77054, USA
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Krishna P. Bhat
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Center Center, Houston, TX 77030, USA
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77054, USA
| | - Pratip K. Bhattacharya
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77054, USA
- Correspondence:
| |
Collapse
|
20
|
Püschel J, Dubrovska A, Gorodetska I. The Multifaceted Role of Aldehyde Dehydrogenases in Prostate Cancer Stem Cells. Cancers (Basel) 2021; 13:4703. [PMID: 34572930 PMCID: PMC8472046 DOI: 10.3390/cancers13184703] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/27/2021] [Accepted: 09/13/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) are the only tumor cells possessing self-renewal and differentiation properties, making them an engine of tumor progression and a source of tumor regrowth after treatment. Conventional therapies eliminate most non-CSCs, while CSCs often remain radiation and drug resistant, leading to tumor relapse and metastases. Thus, targeting CSCs might be a powerful tool to overcome tumor resistance and increase the efficiency of current cancer treatment strategies. The identification and isolation of the CSC population based on its high aldehyde dehydrogenase activity (ALDH) is widely accepted for prostate cancer (PCa) and many other solid tumors. In PCa, several ALDH genes contribute to the ALDH activity, which can be measured in the enzymatic assay by converting 4, 4-difluoro-4-bora-3a, 4a-diaza-s-indacene (BODIPY) aminoacetaldehyde (BAAA) into the fluorescent product BODIPY-aminoacetate (BAA). Although each ALDH isoform plays an individual role in PCa biology, their mutual functional interplay also contributes to PCa progression. Thus, ALDH proteins are markers and functional regulators of CSC properties, representing an attractive target for cancer treatment. In this review, we discuss the current state of research regarding the role of individual ALDH isoforms in PCa development and progression, their possible therapeutic targeting, and provide an outlook for the future advances in this field.
Collapse
Affiliation(s)
- Jakob Püschel
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany;
| | - Anna Dubrovska
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany;
- National Center for Tumor Diseases (NCT), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01307 Dresden, Germany
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Ielizaveta Gorodetska
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany;
| |
Collapse
|
21
|
Sosnowska M, Kutwin M, Strojny B, Wierzbicki M, Cysewski D, Szczepaniak J, Ficek M, Koczoń P, Jaworski S, Chwalibog A, Sawosz E. Diamond Nanofilm Normalizes Proliferation and Metabolism in Liver Cancer Cells. Nanotechnol Sci Appl 2021; 14:115-137. [PMID: 34511890 PMCID: PMC8420805 DOI: 10.2147/nsa.s322766] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 07/28/2021] [Indexed: 01/10/2023] Open
Abstract
Purpose Surgical resection of hepatocellular carcinoma can be associated with recurrence resulting from the degeneration of residual volume of the liver. The objective was to assess the possibility of using a biocompatible nanofilm, made of a colloid of diamond nanoparticles (nfND), to fill the side after tumour resection and optimize its contact with proliferating liver cells, minimizing their cancerous transformation. Methods HepG2 and C3A liver cancer cells and HS-5 non-cancer cells were used. An aqueous colloid of diamond nanoparticles, which covered the cell culture plate, was used to create the nanofilm. The roughness of the resulting nanofilm was measured by atomic force microscopy. Mitochondrial activity and cell proliferation were measured by XTT and BrdU assays. Cell morphology and a scratch test were used to evaluate the invasiveness of cells. Flow cytometry determined the number of cells within the cell cycle. Protein expression in was measured by mass spectrometry. Results The nfND created a surface with increased roughness and exposed oxygen groups compared with a standard plate. All cell lines were prone to settling on the nanofilm, but cancer cells formed more relaxed clusters. The surface compatibility was dependent on the cell type and decreased in the order C3A >HepG2 >HS-5. The invasion was reduced in cancer lines with the greatest effect on the C3A line, reducing proliferation and increasing the G2/M cell population. Among the proteins with altered expression, membrane and nuclear proteins dominated. Conclusion In vitro studies demonstrated the antiproliferative properties of nfND against C3A liver cancer cells. At the same time, the need to personalize potential therapy was indicated due to the differential protein synthetic responses in C3A vs HepG2 cells. We documented that nfND is a source of signals capable of normalizing the expression of many intracellular proteins involved in the transformation to non-cancerous cells.
Collapse
Affiliation(s)
- Malwina Sosnowska
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland
| | - Marta Kutwin
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland
| | - Barbara Strojny
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland
| | - Mateusz Wierzbicki
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland
| | - Dominik Cysewski
- Spectrometry Laboratory, Institute of Biochemistry and Biophysics, Polish Academy of Science, Warsaw, Poland
| | - Jarosław Szczepaniak
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland
| | - Mateusz Ficek
- Department of Metrology and Optoelectronics, Gdansk University of Technology, Gdansk, Poland
| | - Piotr Koczoń
- Department of Chemistry, Institute of Food Sciences, Warsaw University of Life Sciences, Warsaw, Poland
| | - Sławomir Jaworski
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland
| | - André Chwalibog
- Department of Veterinary and Animal, Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Ewa Sawosz
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland
| |
Collapse
|
22
|
Liu Y, Yang Y, Yao R, Hu Y, Liu P, Lian S, Lv H, Xu B, Li S. Dietary supplementary glutamine and L-carnitine enhanced the anti-cold stress of Arbor Acres broilers. Arch Anim Breed 2021; 64:231-243. [PMID: 34159254 PMCID: PMC8209504 DOI: 10.5194/aab-64-231-2021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 04/01/2021] [Indexed: 01/16/2023] Open
Abstract
Newborn poultry in cold regions often suffer from cold stress,
causing a series of changes in their physiology and metabolism, leading to
slow growth and decreased production performance. However, a single
anti-stress substance cannot completely or maximally eliminate or alleviate
the various effects of cold stress on animals. Therefore, the effects of the
supplemented glutamine and L-carnitine on broilers under low temperature
were evaluated in this study. Broilers were randomly allocated into 16
groups which were respectively fed with different levels of glutamine and
L-carnitine according to the L16 (45) orthogonal experimental
design for 3 weeks (the first week is the adaptive feeding period; the
second and third weeks are the cold exposure period). Growth performance
was recorded, and blood samples were collected during cold exposure. The
results showed the supplementation had altered the plasma parameters, growth
performance and cold-induced oxidative stress. The increase of
corticosterone and suppression of thyroid hormone was ameliorated.
Supplemented groups had lower daily feed intake and feed-to-gain ratio, higher
daily weight gain and better relative weights of immune organs. Plasma
glucose, total protein, blood urea nitrogen and alkaline phosphatase
changed as well. Oxidative stress was mollified due to the improved
activities of superoxide dismutase and glutathione peroxidase, heightened
total antioxidant capacity and stable malondialdehyde. Dietary glutamine and
L-carnitine improve the growth performance, nutritional status and cold
stress response of broilers at low temperature, and their interaction
occurred.
Collapse
Affiliation(s)
- Yang Liu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, 163319, PR China
| | - Yuying Yang
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, 163319, PR China
| | - Ruizhi Yao
- College of Animal Science and Technology, Inner Mongolia University for Nationalities, Tongliao, 028000, PR China
| | - Yajie Hu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, 163319, PR China
| | - Peng Liu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, 163319, PR China
| | - Shuai Lian
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, 163319, PR China
| | - Hongming Lv
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, 163319, PR China
| | - Bin Xu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, 163319, PR China
| | - Shize Li
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, 163319, PR China
| |
Collapse
|
23
|
NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications. Signal Transduct Target Ther 2020; 5:231. [PMID: 33028807 PMCID: PMC7542157 DOI: 10.1038/s41392-020-00326-0] [Citation(s) in RCA: 288] [Impact Index Per Article: 57.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 08/09/2020] [Accepted: 09/14/2020] [Indexed: 02/08/2023] Open
Abstract
Nicotinamide adenine dinucleotide phosphate (NADPH) is an essential electron donor in all organisms, and provides the reducing power for anabolic reactions and redox balance. NADPH homeostasis is regulated by varied signaling pathways and several metabolic enzymes that undergo adaptive alteration in cancer cells. The metabolic reprogramming of NADPH renders cancer cells both highly dependent on this metabolic network for antioxidant capacity and more susceptible to oxidative stress. Modulating the unique NADPH homeostasis of cancer cells might be an effective strategy to eliminate these cells. In this review, we summarize the current existing literatures on NADPH homeostasis, including its biological functions, regulatory mechanisms and the corresponding therapeutic interventions in human cancers, providing insights into therapeutic implications of targeting NADPH metabolism and the associated mechanism for cancer therapy.
Collapse
|
24
|
Liu W, Wang Q, Chang J. Global metabolomic profiling of trastuzumab resistant gastric cancer cells reveals major metabolic pathways and metabolic signatures based on UHPLC-Q exactive-MS/MS. RSC Adv 2019; 9:41192-41208. [PMID: 35540060 PMCID: PMC9076425 DOI: 10.1039/c9ra06607a] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 11/26/2019] [Indexed: 12/15/2022] Open
Abstract
Resistance mechanism exploration has become an urgent need owing to the widespread trastuzumab resistance in gastric cancer. In this study, UHPLC-Q exactive MS/MS was carried out to characterize the metabolic profiles of human gastric cancer cell lines NCI N87, MKN45 (trastuzumab-sensitive) and NCI N87/R, MKN45/R (trastuzumab-resistant), respectively. Metabolic signatures and different metabolites were identified using multivariate in combination with univariate analysis. Integrated pathway enrichment analysis was executed using MetaboAnalyst and KEGG metabolic libraries to analyze the altered metabolic pathways in trastuzumab resistant cells. A total of 79 and 75 different metabolites were positively identified by utilizing authentic standards in NCI N87/R and MKN45/R cells, respectively. Furthermore, enrichment analysis demonstrated that seven metabolic pathways in NCI N87/R cells and five in MKN45/R cells were significantly changed. These pathways are involved in amino acid, nucleotide, carbohydrate, cofactor and vitamin metabolism, of which alanine, aspartate and glutamate metabolism displayed the highest pathway impact and lower P value both in NCI N87/R and MKN45/R cells. Moreover, we constructed a metabolomics-proteomics network between substantially altered metabolites and target genes which revealed citrate being regulated by citrate synthase and ACLY, while proline regulation was due to EPRS, PYCRL and PYCR1/2, respectively. Overall, our findings disclose prominent alterations of metabolic signatures in NCI N87/R and MKN45/R cells when compared with the parent cells which are crucial for understanding of underlying mechanisms of resistance and for developing strategies to overcome trastuzumab resistance.
Collapse
Affiliation(s)
- Wenhu Liu
- School of Basic Medical Sciences, North Sichuan Medical College Nanchong 637100 China
- School of Pharmacy, North Sichuan Medical College Nanchong 637100 China
| | - Qiang Wang
- Department of Laboratory Medicine, Affiliated Hospital of North Sichuan Medical College, Faculty of Laboratory Medicine, Center for Translational Medicine, North Sichuan Medical College Nanchong 637000 China
| | - Jinxia Chang
- School of Basic Medical Sciences, North Sichuan Medical College Nanchong 637100 China
| |
Collapse
|
25
|
Wang Y, Yang S, Zhao J, Du W, Liang Y, Wang C, Zhou F, Tian Y, Ma Q. Using Machine Learning to Measure Relatedness Between Genes: A Multi-Features Model. Sci Rep 2019; 9:4192. [PMID: 30862804 PMCID: PMC6414665 DOI: 10.1038/s41598-019-40780-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 02/19/2019] [Indexed: 12/20/2022] Open
Abstract
Measuring conditional relatedness between a pair of genes is a fundamental technique and still a significant challenge in computational biology. Such relatedness can be assessed by gene expression similarities while suffering high false discovery rates. Meanwhile, other types of features, e.g., prior-knowledge based similarities, is only viable for measuring global relatedness. In this paper, we propose a novel machine learning model, named Multi-Features Relatedness (MFR), for accurately measuring conditional relatedness between a pair of genes by incorporating expression similarities with prior-knowledge based similarities in an assessment criterion. MFR is used to predict gene-gene interactions extracted from the COXPRESdb, KEGG, HPRD, and TRRUST databases by the 10-fold cross validation and test verification, and to identify gene-gene interactions collected from the GeneFriends and DIP databases for further verification. The results show that MFR achieves the highest area under curve (AUC) values for identifying gene-gene interactions in the development, test, and DIP datasets. Specifically, it obtains an improvement of 1.1% on average of precision for detecting gene pairs with both high expression similarities and high prior-knowledge based similarities in all datasets, comparing to other linear models and coexpression analysis methods. Regarding cancer gene networks construction and gene function prediction, MFR also obtains the results with more biological significances and higher average prediction accuracy, than other compared models and methods. A website of the MFR model and relevant datasets can be accessed from http://bmbl.sdstate.edu/MFR.
Collapse
Affiliation(s)
- Yan Wang
- Key Laboratory of Symbol Computation and Knowledge Engineering of Ministry of Education, College of Computer Science and Technology, Jilin University, Changchun, 130012, China
| | - Sen Yang
- Key Laboratory of Symbol Computation and Knowledge Engineering of Ministry of Education, College of Computer Science and Technology, Jilin University, Changchun, 130012, China
| | - Jing Zhao
- Population Health Group, Sanford Research, Sioux Falls, SD, 57104, USA.,Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, 57105, USA
| | - Wei Du
- Key Laboratory of Symbol Computation and Knowledge Engineering of Ministry of Education, College of Computer Science and Technology, Jilin University, Changchun, 130012, China
| | - Yanchun Liang
- Key Laboratory of Symbol Computation and Knowledge Engineering of Ministry of Education, College of Computer Science and Technology, Jilin University, Changchun, 130012, China.,Zhuhai Laboratory of Key Laboratory of Symbol Computation and Knowledge Engineering of Ministry of Education, Department of Computer Science and Technology, Zhuhai College of Jilin University, Zhuhai, 519041, China
| | - Cankun Wang
- Bioinformatics and Mathematical Biosciences Lab, Department of Agronomy, Horticulture, and Plant Science, Department of Mathematics and Statistics, South Dakota State University, Brookings, SD, 57006, USA
| | - Fengfeng Zhou
- Key Laboratory of Symbol Computation and Knowledge Engineering of Ministry of Education, College of Computer Science and Technology, Jilin University, Changchun, 130012, China
| | - Yuan Tian
- Key Laboratory of Symbol Computation and Knowledge Engineering of Ministry of Education, College of Computer Science and Technology, Jilin University, Changchun, 130012, China. .,School of Artificial Intelligence, Jilin University, Changchun, 130012, China.
| | - Qin Ma
- Bioinformatics and Mathematical Biosciences Lab, Department of Agronomy, Horticulture, and Plant Science, Department of Mathematics and Statistics, South Dakota State University, Brookings, SD, 57006, USA. .,Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
| |
Collapse
|
26
|
Dong J, Zheng S, Yang X, Song X. Cell proliferation in kidney carcinoma is inhibited by lncRNA GASL1. EUR J INFLAMM 2019. [DOI: 10.1177/2058739219854598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Long noncoding RNA (lncRNA) GASL1 was identified as a novel lncRNA, which plays an important role in the proliferation and apoptosis of cells. This study aimed to compare the expression of GASL1 mRNA in kidney cancer cells and normal cells and detect the biological role of GASL1 in kidney cancer cell line A498. Polymerase chain reaction (PCR) was performed to examine the expression of GASL1 mRNA in kidney cancer tissues, normal tissues, and the cell lines. GASL1 overexpression was achieved in kidney cancer cell lines A498 through transfection. MTT was used to detect the effects of GASL1 overexpression in A498 cells. GASL1 mRNA was significantly overexpressed in adjacent normal tissues compared with renal cell carcinoma. The expression of GASL1 is lower in kidney cancer cell lines than in normal kidney epithelium cell line HREpiC. Overexpression of GASL1 inhibits the proliferation of renal carcinoma cell lines. GASL1 mRNA was down-regulated in kidney cancer tissues and may play a role in kidney cancer cell proliferation.
Collapse
Affiliation(s)
- Jianping Dong
- Department of Uropoiesis Surgical, Shouguang People’s Hospital, Shouguang, China
| | - Shiping Zheng
- Department of Uropoiesis Surgical, Shouguang People’s Hospital, Shouguang, China
| | - Xiaoyan Yang
- Department of Uropoiesis Surgical, Shouguang People’s Hospital, Shouguang, China
| | - Xiuyan Song
- Department of Uropoiesis Surgical, Shouguang People’s Hospital, Shouguang, China
| |
Collapse
|
27
|
Rona GB, Almeida NP, Santos GC, Fidalgo TKS, Almeida FCL, Eleutherio ECA, Pinheiro AS. 1
H NMR metabolomics reveals increased glutaminolysis upon overexpression of NSD3s or Pdp3 in
Saccharomyces cerevisiae. J Cell Biochem 2018; 120:5377-5385. [DOI: 10.1002/jcb.27816] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 09/12/2018] [Indexed: 12/16/2022]
Affiliation(s)
- Germana B Rona
- Department of Biochemistry Institute of Chemistry, Federal University of Rio de Janeiro Rio de Janeiro Brazil
| | - Natalia P Almeida
- Department of Biochemistry Institute of Chemistry, Federal University of Rio de Janeiro Rio de Janeiro Brazil
| | - Gilson C Santos
- National Center for Nuclear Magnetic Resonance Jiri Jonas (CNRMN), Structural Biology Program, Medical Biochemistry Institute and Center for Structural Biology and Bioimaging I (CENABIO I), Federal University of Rio de Janeiro Rio de Janeiro Brazil
| | - Tatiana KS Fidalgo
- Department of Preventive and Community Dentistry, School of Dentistry, State University of Rio de Janeiro Rio de Janeiro Brazil
| | - Fabio CL Almeida
- National Center for Nuclear Magnetic Resonance Jiri Jonas (CNRMN), Structural Biology Program, Medical Biochemistry Institute and Center for Structural Biology and Bioimaging I (CENABIO I), Federal University of Rio de Janeiro Rio de Janeiro Brazil
| | - Elis CA Eleutherio
- Department of Biochemistry Institute of Chemistry, Federal University of Rio de Janeiro Rio de Janeiro Brazil
| | - Anderson S Pinheiro
- Department of Biochemistry Institute of Chemistry, Federal University of Rio de Janeiro Rio de Janeiro Brazil
| |
Collapse
|
28
|
Koppula P, Zhang Y, Zhuang L, Gan B. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. Cancer Commun (Lond) 2018; 38:12. [PMID: 29764521 PMCID: PMC5993148 DOI: 10.1186/s40880-018-0288-x] [Citation(s) in RCA: 534] [Impact Index Per Article: 76.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 01/22/2018] [Indexed: 12/23/2022] Open
Abstract
Cancer cells often upregulate nutrient transporters to fulfill their increased biosynthetic and bioenergetic needs, and to maintain redox homeostasis. One nutrient transporter frequently overexpressed in human cancers is the cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11; also known as xCT). SLC7A11 promotes cystine uptake and glutathione biosynthesis, resulting in protection from oxidative stress and ferroptotic cell death. Recent studies have unexpectedly revealed that SLC7A11 also plays critical roles in glutamine metabolism and regulates the glucose and glutamine dependency of cancer cells. This review discusses the roles of SLC7A11 in regulating the antioxidant response and nutrient dependency of cancer cells, explores our current understanding of SLC7A11 regulation in cancer metabolism, and highlights key open questions for future studies in this emerging research area. A deeper understanding of SLC7A11 in cancer metabolism may identify new therapeutic opportunities to target this important amino acid transporter for cancer treatment.
Collapse
Affiliation(s)
- Pranavi Koppula
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.,The University of Texas Graduate School of Biomedical Sciences, 6767 Bertner Ave., Houston, TX, 77030, USA
| | - Yilei Zhang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Li Zhuang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Boyi Gan
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. .,The University of Texas Graduate School of Biomedical Sciences, 6767 Bertner Ave., Houston, TX, 77030, USA. .,Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| |
Collapse
|
29
|
Wang J, Yuan L, Liu X, Wang G, Zhu Y, Qian K, Xiao Y, Wang X. Bioinformatics and functional analyses of key genes and pathways in human clear cell renal cell carcinoma. Oncol Lett 2018; 15:9133-9141. [PMID: 29805645 PMCID: PMC5958663 DOI: 10.3892/ol.2018.8473] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 12/11/2017] [Indexed: 02/06/2023] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. The present study was conducted to explore the mechanisms and identify the potential target genes for ccRCC using bioinformatics analysis. The microarray data of GSE15641 were screened on Gene-Cloud of Biotechnology Information (GCBI). A total of 32 ccRCC samples and 23 normal kidney samples were used to identify differentially expressed genes (DEGs) between them. Subsequently, the clustering analysis and functional enrichment analysis of these DEGs were performed, followed by protein-protein interaction (PPI) network, and pathway relation network. Additionally, the most significant module based on PPI network was selected, and the genes in the module were identified as hub genes. Furthermore, transcriptional level, translational level and survival analyses of hub genes were performed to verify the results. A total of 805 genes, 403 upregulated and 402 downregulated, were differentially expressed in ccRCC samples compared with normal controls. The subsequent bioinformatics analysis indicated that the small molecule metabolic process and the metabolic pathway were significantly enriched. A total of 7 genes, including membrane metallo-endopeptidase (MME), albumin (ALB), cadherin 1 (CDH1), prominin 1 (ROM1), chemokine (C-X-C motif) ligand 12 (CXCL12), protein tyrosine phosphatase receptor type C (PTPRC) and intercellular adhesion molecule 1 (ICAM1) were identified as hub genes. In brief, the present study indicated that these candidate genes and pathways may aid in deciphering the molecular mechanisms underlying the development of ccRCC, and may be used as therapeutic targets and diagnostic biomarkers of ccRCC.
Collapse
Affiliation(s)
- Jinxing Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Lushun Yuan
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Xingnian Liu
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Gang Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Yuan Zhu
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.,Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Kaiyu Qian
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.,Department of Urology, The Fifth Hospital of Wuhan, Wuhan, Hubei 430071, P.R. China.,Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Yu Xiao
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.,Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.,Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Xinghuan Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| |
Collapse
|