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1
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Camacho M, Vázquez-López C, Valero C, Holgado A, Terra X, Avilés-Jurado FX, León X. Transcriptional expression of SLC16A7 as a biomarker of occult lymph node metastases in patients with head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol 2024; 281:6637-6644. [PMID: 39215860 DOI: 10.1007/s00405-024-08882-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 07/29/2024] [Indexed: 09/04/2024]
Abstract
PURPOSE Glucose is the main energy substrate of tumor cells. This study aims to assess whether the transcriptional expression of glucose metabolism-related genes is associated with occult lymph node metastases in head and neck squamous cell carcinoma (HNSCC) patients. METHODS We examined the transcriptional expression of a panel of glucose metabolism-related genes in a cohort of 53 patients with HNSCC without cervical lymph node involvement at the time of diagnosis (cN0) and subsequently treated with elective neck dissection. RESULTS Occult lymph node metastases were found in 37.7% (n = 20) of the patients. Among the analyzed genes, SLC16A7 exhibited the strongest association with the presence of occult lymph node metastases. Patients with occult lymph node metastases (cN0/pN +) had significantly lower SLC16A7 expression values (p = 0.001). Patients with low SLC16A7 expression (n = 17, 32.1%) had a frequency of occult lymph node metastases of 76.5%, while for patients with high SLCA16A7 expression (n = 36, 67.9%) it was 19.4% (P = 0.0001). A multivariable analysis showed that patients with low expression of SLC16A7 had a 12.6 times higher risk of developing occult lymph node metastases. CONCLUSION cN0 HNSCC patients with low SLC16A7 expression had a higher risk of occult lymph node metastases.
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Affiliation(s)
- Mercedes Camacho
- Genomics of Complex Diseases. Institut de Recerca, IIB Sant Pau, Barcelona, Spain
| | - Cristina Vázquez-López
- Otorhinolaryngology Head-Neck Surgery Department, Hospital de La Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
| | - Cristina Valero
- Otorhinolaryngology Head-Neck Surgery Department, Hospital de La Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Anna Holgado
- Otorhinolaryngology Head-Neck Surgery Department, Hospital de La Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ximena Terra
- MoBioFood Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira I Virgili, Tarragona, Spain
| | - Francesc Xavier Avilés-Jurado
- Otorhinolaryngology Head-Neck Surgery Department. Hospital Clínic de Barcelona. IDIBAPS Universitat de Barcelona, Barcelona, Spain
| | - Xavier León
- Otorhinolaryngology Head-Neck Surgery Department, Hospital de La Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
- Center On Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain
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2
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Duan Y, Zhan H, Wang Q, Li B, Gao H, Liu D, Xu Q, Gao X, Liu Z, Gao P, Wei G, Wang Y. Integrated Lactylome Characterization Reveals the Molecular Dynamics of Protein Regulation in Gastrointestinal Cancers. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2400227. [PMID: 39018247 PMCID: PMC11425215 DOI: 10.1002/advs.202400227] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 05/19/2024] [Indexed: 07/19/2024]
Abstract
Lysine lactylation (Kla) plays a vital role in several physiological processes. However, the cancer-specific modulation of Kla in gastrointestinal (GI) tumors requires systematic elucidation. Here, global lactylome profiling of cancerous and adjacent tissues is conducted from 40 patients with GI cancer and identified 11698 Kla sites. Lactylome integration revealed that Kla affects proteins involved in hallmark cancer processes, including epigenetic rewiring, metabolic perturbations, and genome instability. Moreover, the study revealed pan-cancer patterns of Kla alterations, among which 37 Kla sites are consistently upregulated in all four GI cancers and are involved in gene regulation. It is further verified that lactylation of CBX3 at K10 mediates its interaction of CBX3 with the epigenetic marker H3K9me3 and facilitates GI cancer progression. Overall, this study provides an invaluable resource for understanding the lactylome landscape in GI cancers, which may provide new paths for drug discovery for these devastating diseases.
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Affiliation(s)
- Yangmiao Duan
- Key Laboratory for Experimental Teratology of the Ministry of Education, Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Hanxiang Zhan
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China
| | - Qin Wang
- Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China
| | - Bohao Li
- Key Laboratory for Experimental Teratology of the Ministry of Education, Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Huiru Gao
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, China
| | - Duanrui Liu
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Qinchen Xu
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, China
| | - Xin Gao
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China
| | - Zhenya Liu
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China
| | - Peng Gao
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Guangwei Wei
- Key Laboratory for Experimental Teratology of the Ministry of Education, Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Yunshan Wang
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
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Wang FS, Zhang HX. Identification of Anticancer Enzymes and Biomarkers for Hepatocellular Carcinoma through Constraint-Based Modeling. Molecules 2024; 29:2594. [PMID: 38893469 PMCID: PMC11173608 DOI: 10.3390/molecules29112594] [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: 04/12/2024] [Revised: 05/26/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
Hepatocellular carcinoma (HCC) results in the abnormal regulation of cellular metabolic pathways. Constraint-based modeling approaches can be utilized to dissect metabolic reprogramming, enabling the identification of biomarkers and anticancer targets for diagnosis and treatment. In this study, two genome-scale metabolic models (GSMMs) were reconstructed by employing RNA sequencing expression patterns of hepatocellular carcinoma (HCC) and their healthy counterparts. An anticancer target discovery (ACTD) framework was integrated with the two models to identify HCC targets for anticancer treatment. The ACTD framework encompassed four fuzzy objectives to assess both the suppression of cancer cell growth and the minimization of side effects during treatment. The composition of a nutrient may significantly affect target identification. Within the ACTD framework, ten distinct nutrient media were utilized to assess nutrient uptake for identifying potential anticancer enzymes. The findings revealed the successful identification of target enzymes within the cholesterol biosynthetic pathway using a cholesterol-free cell culture medium. Conversely, target enzymes in the cholesterol biosynthetic pathway were not identified when the nutrient uptake included a cholesterol component. Moreover, the enzymes PGS1 and CRL1 were detected in all ten nutrient media. Additionally, the ACTD framework comprises dual-group representations of target combinations, pairing a single-target enzyme with an additional nutrient uptake reaction. Additionally, the enzymes PGS1 and CRL1 were identified across the ten-nutrient media. Furthermore, the ACTD framework encompasses two-group representations of target combinations involving the pairing of a single-target enzyme with an additional nutrient uptake reaction. Computational analysis unveiled that cell viability for all dual-target combinations exceeded that of their respective single-target enzymes. Consequently, integrating a target enzyme while adjusting an additional exchange reaction could efficiently mitigate cell proliferation rates and ATP production in the treated cancer cells. Nevertheless, most dual-target combinations led to lower side effects in contrast to their single-target counterparts. Additionally, differential expression of metabolites between cancer cells and their healthy counterparts were assessed via parsimonious flux variability analysis employing the GSMMs to pinpoint potential biomarkers. The variabilities of the fluxes and metabolite flow rates in cancer and healthy cells were classified into seven categories. Accordingly, two secretions and thirteen uptakes (including eight essential amino acids and two conditionally essential amino acids) were identified as potential biomarkers. The findings of this study indicated that cancer cells exhibit a higher uptake of amino acids compared with their healthy counterparts.
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Affiliation(s)
- Feng-Sheng Wang
- Department of Chemical Engineering, National Chung Cheng University, Chiayi 621301, Taiwan;
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Masci D, Puxeddu M, Silvestri R, La Regina G. Metabolic Rewiring in Cancer: Small Molecule Inhibitors in Colorectal Cancer Therapy. Molecules 2024; 29:2110. [PMID: 38731601 PMCID: PMC11085455 DOI: 10.3390/molecules29092110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/16/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Alterations in cellular metabolism, such as dysregulation in glycolysis, lipid metabolism, and glutaminolysis in response to hypoxic and low-nutrient conditions within the tumor microenvironment, are well-recognized hallmarks of cancer. Therefore, understanding the interplay between aerobic glycolysis, lipid metabolism, and glutaminolysis is crucial for developing effective metabolism-based therapies for cancer, particularly in the context of colorectal cancer (CRC). In this regard, the present review explores the complex field of metabolic reprogramming in tumorigenesis and progression, providing insights into the current landscape of small molecule inhibitors targeting tumorigenic metabolic pathways and their implications for CRC treatment.
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Affiliation(s)
- Domiziana Masci
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy;
| | - Michela Puxeddu
- Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (R.S.)
| | - Romano Silvestri
- Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (R.S.)
| | - Giuseppe La Regina
- Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (R.S.)
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Liu J, Lu X, Zeng S, Fu R, Wang X, Luo L, Huang T, Deng X, Zheng H, Ma S, Ning D, Zong L, Lin SH, Zhang Y. ATF3-CBS signaling axis coordinates ferroptosis and tumorigenesis in colorectal cancer. Redox Biol 2024; 71:103118. [PMID: 38490069 PMCID: PMC10958616 DOI: 10.1016/j.redox.2024.103118] [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: 01/26/2024] [Revised: 03/02/2024] [Accepted: 03/06/2024] [Indexed: 03/17/2024] Open
Abstract
The induction of ferroptosis is promising for cancer therapy. However, the mechanisms enabling cancer cells to evade ferroptosis, particularly in low-cystine environments, remain elusive. Our study delves into the intricate regulatory mechanisms of Activating transcription factor 3 (ATF3) on Cystathionine β-synthase (CBS) under cystine deprivation stress, conferring resistance to ferroptosis in colorectal cancer (CRC) cells. Additionally, our findings establish a positively correlation between this signaling axis and CRC progression, suggesting its potential as a therapeutic target. Mechanistically, ATF3 positively regulates CBS to resist ferroptosis under cystine deprivation stress. In contrast, the suppression of CBS sensitizes CRC cells to ferroptosis through targeting the mitochondrial tricarboxylic acid (TCA) cycle. Notably, our study highlights that the ATF3-CBS signaling axis enhances ferroptosis-based CRC cancer therapy. Collectively, the findings reveal that the ATF3-CBS signaling axis is the primary feedback pathway in ferroptosis, and blocking this axis could be a potential therapeutic approach for colorectal cancer.
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Affiliation(s)
- Junjia Liu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Xinyi Lu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Siyu Zeng
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Rong Fu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Xindong Wang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Lingtao Luo
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, 361102, China
| | - Ting Huang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China; School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Xusheng Deng
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Hualei Zheng
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Shaoqian Ma
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Dan Ning
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Lili Zong
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Shu-Hai Lin
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China; National Institute for Data Science in Health and Medicine Engineering, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Yongyou Zhang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China; National Institute for Data Science in Health and Medicine Engineering, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
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6
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Martínez-Orts M, Pujals S. Responsive Supramolecular Polymers for Diagnosis and Treatment. Int J Mol Sci 2024; 25:4077. [PMID: 38612886 PMCID: PMC11012635 DOI: 10.3390/ijms25074077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 04/02/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024] Open
Abstract
Stimuli-responsive supramolecular polymers are ordered nanosized materials that are held together by non-covalent interactions (hydrogen-bonding, metal-ligand coordination, π-stacking and, host-guest interactions) and can reversibly undergo self-assembly. Their non-covalent nature endows supramolecular polymers with the ability to respond to external stimuli (temperature, light, ultrasound, electric/magnetic field) or environmental changes (temperature, pH, redox potential, enzyme activity), making them attractive candidates for a variety of biomedical applications. To date, supramolecular research has largely evolved in the development of smart water-soluble self-assemblies with the aim of mimicking the biological function of natural supramolecular systems. Indeed, there is a wide variety of synthetic biomaterials formulated with responsiveness to control and trigger, or not to trigger, aqueous self-assembly. The design of responsive supramolecular polymers ranges from the use of hydrophobic cores (i.e., benzene-1,3,5-tricarboxamide) to the introduction of macrocyclic hosts (i.e., cyclodextrins). In this review, we summarize the most relevant advances achieved in the design of stimuli-responsive supramolecular systems used to control transport and release of both diagnosis agents and therapeutic drugs in order to prevent, diagnose, and treat human diseases.
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Affiliation(s)
| | - Silvia Pujals
- Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain;
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Zhang Y, Song H, Li M, Lu P. Histone lactylation bridges metabolic reprogramming and epigenetic rewiring in driving carcinogenesis: Oncometabolite fuels oncogenic transcription. Clin Transl Med 2024; 14:e1614. [PMID: 38456209 PMCID: PMC10921234 DOI: 10.1002/ctm2.1614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/13/2024] [Accepted: 02/18/2024] [Indexed: 03/09/2024] Open
Abstract
Heightened lactate production in cancer cells has been linked to various cellular mechanisms such as angiogenesis, hypoxia, macrophage polarisation and T-cell dysfunction. The lactate-induced lactylation of histone lysine residues is noteworthy, as it functions as an epigenetic modification that directly augments gene transcription from chromatin. This epigenetic modification originating from lactate effectively fosters a reliance on transcription, thereby expediting tumour progression and development. Herein, this review explores the correlation between histone lactylation and cancer characteristics, revealing histone lactylation as an innovative epigenetic process that enhances the vulnerability of cells to malignancy. Moreover, it is imperative to acknowledge the paramount importance of acknowledging innovative therapeutic methodologies for proficiently managing cancer by precisely targeting lactate signalling. This comprehensive review illuminates a crucial yet inadequately investigated aspect of histone lactylation, providing valuable insights into its clinical ramifications and prospective therapeutic interventions centred on lactylation.
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Affiliation(s)
- Yu Zhang
- Department of Clinical MedicineXuzhou Medical UniversityXuzhouJiangsuChina
| | - Hang Song
- Department of OphthalmologyPeking Union Medical College HospitalBeijingChina
| | - Meili Li
- Department of OphthalmologyEye Disease Prevention and Treatment Institute of Xuzhou, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical UniversityXuzhou First People's HospitalXuzhouJiangsuChina
| | - Peirong Lu
- Department of OphthalmologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
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Ishteyaque S, Singh G, Yadav KS, Verma S, Sharma RK, Sen S, Srivastava AK, Mitra K, Lahiri A, Bawankule DU, Rath SK, Kumar D, Mugale MN. Cooperative STAT3-NFkB signaling modulates mitochondrial dysfunction and metabolic profiling in hepatocellular carcinoma. Metabolism 2024; 152:155771. [PMID: 38184165 DOI: 10.1016/j.metabol.2023.155771] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/12/2023] [Accepted: 12/27/2023] [Indexed: 01/08/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) continues to pose a significant health challenge and is often diagnosed at advanced stages. Metabolic reprogramming is a hallmark of many cancer types, including HCC and it involves alterations in various metabolic or nutrient-sensing pathways within liver cells to facilitate the rapid growth and progression of tumours. However, the role of STAT3-NFκB in metabolic reprogramming is still not clear. APPROACH AND RESULTS Diethylnitrosamine (DEN) administered animals showed decreased body weight and elevated level of serum enzymes. Also, Transmission electron microscopy (TEM) analysis revealed ultrastructural alterations. Increased phosphorylated signal transducer and activator of transcription-3 (p-STAT3), phosphorylated nuclear factor kappa B (p-NFκβ), dynamin related protein 1 (Drp-1) and alpha-fetoprotein (AFP) expression enhance the carcinogenicity as revealed in immunohistochemistry (IHC). The enzyme-linked immunosorbent assay (ELISA) concentration of IL-6 was found to be elevated in time dependent manner both in blood serum and liver tissue. Moreover, immunoblot analysis showed increased level of p-STAT3, p-NFκβ and IL-6 stimulated the upregulation of mitophagy proteins such as Drp-1, Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK-1). Meanwhile, downregulation of Poly [ADP-ribose] polymerase 1 (PARP-1) and cleaved caspase 3 suppresses apoptosis and enhanced expression of AFP supports tumorigenesis. The mRNA level of STAT3 and Drp-1 was also found to be significantly increased. Furthermore, we performed high-field 800 MHz Nuclear Magnetic Resonance (NMR) based tissue and serum metabolomics analysis to identify metabolic signatures associated with the progression of liver cancer. The metabolomics findings revealed aberrant metabolic alterations in liver tissue and serum of 75th and 105th days of intervention groups in comparison to control, 15th and 45th days of intervention groups. Tissue metabolomics analysis revealed the accumulation of succinate in the liver tissue samples, whereas, serum metabolomics analysis revealed significantly decreased circulatory levels of ketone bodies (such as 3-hydroxybutyrate, acetate, acetone, etc.) and membrane metabolites suggesting activated ketolysis in advanced stages of liver cancer. CONCLUSION STAT3-NFκβ signaling axis has a significant role in mitochondrial dysfunction and metabolic alterations in the development of HCC.
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Affiliation(s)
- Sharmeen Ishteyaque
- Division of Cancer Biology CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Gurvinder Singh
- Department of Advanced Spectroscopy and Imaging, Centre of Biomedical Research (CBMR), SGPGIMS Campus, Raebareli Road, Lucknow-226014, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Karan Singh Yadav
- Division of Cancer Biology CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Smriti Verma
- Division of Cancer Biology CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Rakesh Kumar Sharma
- Sophisticated Analytical Instrument Facility and Research Division CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Sumati Sen
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, Uttar Pradesh 226015, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Anurag Kumar Srivastava
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India
| | - Kalyan Mitra
- Sophisticated Analytical Instrument Facility and Research Division CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Amit Lahiri
- Pharmacology Division, CSIR - Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Dnyaneshwar U Bawankule
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, Uttar Pradesh 226015, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Srikanta Kumar Rath
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India
| | - Dinesh Kumar
- Department of Advanced Spectroscopy and Imaging, Centre of Biomedical Research (CBMR), SGPGIMS Campus, Raebareli Road, Lucknow-226014, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
| | - Madhav Nilakanth Mugale
- Division of Cancer Biology CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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9
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Tomar MS, Kumar A, Shrivastava A. Mitochondrial metabolism as a dynamic regulatory hub to malignant transformation and anti-cancer drug resistance. Biochem Biophys Res Commun 2024; 694:149382. [PMID: 38128382 DOI: 10.1016/j.bbrc.2023.149382] [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: 08/17/2023] [Revised: 12/02/2023] [Accepted: 12/11/2023] [Indexed: 12/23/2023]
Abstract
Glycolysis is the fundamental cellular process that permits cancer cells to convert energy and grow anaerobically. Recent developments in molecular biology have made it evident that mitochondrial respiration is critical to tumor growth and treatment response. As the principal organelle of cellular energy conversion, mitochondria can rapidly alter cellular metabolic processes, thereby fueling malignancies and contributing to treatment resistance. This review emphasizes the significance of mitochondrial biogenesis, turnover, DNA copy number, and mutations in bioenergetic system regulation. Tumorigenesis requires an intricate cascade of metabolic pathways that includes rewiring of the tricarboxylic acid (TCA) cycle, electron transport chain and oxidative phosphorylation, supply of intermediate metabolites of the TCA cycle through amino acids, and the interaction between mitochondria and lipid metabolism. Cancer recurrence or resistance to therapy often results from the cooperation of several cellular defense mechanisms, most of which are connected to mitochondria. Many clinical trials are underway to assess the effectiveness of inhibiting mitochondrial respiration as a potential cancer therapeutic. We aim to summarize innovative strategies and therapeutic targets by conducting a comprehensive review of recent studies on the relationship between mitochondrial metabolism, tumor development and therapeutic resistance.
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Affiliation(s)
- Manendra Singh Tomar
- Center for Advance Research, Faculty of Medicine, King George's Medical University, Lucknow, 226003, Uttar Pradesh, India
| | - Ashok Kumar
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS) Bhopal, Saket Nagar, Bhopal, 462020, Madhya Pradesh, India
| | - Ashutosh Shrivastava
- Center for Advance Research, Faculty of Medicine, King George's Medical University, Lucknow, 226003, Uttar Pradesh, India.
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Griesemer M, Navid A. Uses of Multi-Objective Flux Analysis for Optimization of Microbial Production of Secondary Metabolites. Microorganisms 2023; 11:2149. [PMID: 37763993 PMCID: PMC10536367 DOI: 10.3390/microorganisms11092149] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 09/29/2023] Open
Abstract
Secondary metabolites are not essential for the growth of microorganisms, but they play a critical role in how microbes interact with their surroundings. In addition to this important ecological role, secondary metabolites also have a variety of agricultural, medicinal, and industrial uses, and thus the examination of secondary metabolism of plants and microbes is a growing scientific field. While the chemical production of certain secondary metabolites is possible, industrial-scale microbial production is a green and economically attractive alternative. This is even more true, given the advances in bioengineering that allow us to alter the workings of microbes in order to increase their production of compounds of interest. This type of engineering requires detailed knowledge of the "chassis" organism's metabolism. Since the resources and the catalytic capacity of enzymes in microbes is finite, it is important to examine the tradeoffs between various bioprocesses in an engineered system and alter its working in a manner that minimally perturbs the robustness of the system while allowing for the maximum production of a product of interest. The in silico multi-objective analysis of metabolism using genome-scale models is an ideal method for such examinations.
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Affiliation(s)
| | - Ali Navid
- Lawrence Livermore National Laboratory, Biosciences & Biotechnology Division, Physical & Life Sciences Directorate, Livermore, CA 94550, USA
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11
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Shimpi AA, Tan ML, Vilkhovoy M, Dai D, Roberts LM, Kuo J, Huang L, Varner JD, Paszek M, Fischbach C. Convergent Approaches to Delineate the Metabolic Regulation of Tumor Invasion by Hyaluronic Acid Biosynthesis. Adv Healthc Mater 2023; 12:e2202224. [PMID: 36479976 PMCID: PMC10238572 DOI: 10.1002/adhm.202202224] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/21/2022] [Indexed: 12/13/2022]
Abstract
Metastasis is the leading cause of breast cancer-related deaths and is often driven by invasion and cancer-stem like cells (CSCs). Both the CSC phenotype and invasion are associated with increased hyaluronic acid (HA) production. How these independent observations are connected, and which role metabolism plays in this process, remains unclear due to the lack of convergent approaches integrating engineered model systems, computational tools, and cancer biology. Using microfluidic invasion models, metabolomics, computational flux balance analysis, and bioinformatic analysis of patient data, the functional links between the stem-like, invasive, and metabolic phenotype of breast cancer cells as a function of HA biosynthesis are investigated. These results suggest that CSCs are more invasive than non-CSCs and that broad metabolic changes caused by overproduction of HA play a role in this process. Accordingly, overexpression of hyaluronic acid synthases (HAS) 2 or 3 induces a metabolic phenotype that promotes cancer cell stemness and invasion in vitro and upregulates a transcriptomic signature predictive of increased invasion and worse patient survival. This study suggests that HA overproduction leads to metabolic adaptations to satisfy the energy demands for 3D invasion of breast CSCs highlighting the importance of engineered model systems and multidisciplinary approaches in cancer research.
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Affiliation(s)
- Adrian A. Shimpi
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, 14853, USA
| | - Matthew L. Tan
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, 14853, USA
| | - Michael Vilkhovoy
- Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, 14853, USA
| | - David Dai
- Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, 14853, USA
| | - L. Monet Roberts
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, 14853, USA
- Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, 14853, USA
| | - Joe Kuo
- Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, 14853, USA
| | - Lingting Huang
- Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, 14853, USA
| | - Jeffrey D. Varner
- Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, 14853, USA
| | - Matthew Paszek
- Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, 14853, USA
- Kavli Institute at Cornell for Nanoscale Science, Cornell University, Ithaca, New York, 14853, USA
| | - Claudia Fischbach
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, 14853, USA
- Kavli Institute at Cornell for Nanoscale Science, Cornell University, Ithaca, New York, 14853, USA
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12
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Intracellular lifestyle of Chlamydia trachomatis and host-pathogen interactions. Nat Rev Microbiol 2023:10.1038/s41579-023-00860-y. [PMID: 36788308 DOI: 10.1038/s41579-023-00860-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2023] [Indexed: 02/16/2023]
Abstract
In recent years, substantial progress has been made in the understanding of the intracellular lifestyle of Chlamydia trachomatis and how the bacteria establish themselves in the human host. As an obligate intracellular pathogenic bacterium with a strongly reduced coding capacity, C. trachomatis depends on the provision of nutrients from the host cell. In this Review, we summarize the current understanding of how C. trachomatis establishes its intracellular replication niche, how its metabolism functions in the host cell, how it can defend itself against the cell autonomous and innate immune response and how it overcomes adverse situations through the transition to a persistent state. In particular, we focus on those processes for which a mechanistic understanding has been achieved.
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13
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Hu C, Xu H, Li Z, Liu D, Zhang S, Fang F, Wang L. Juglone promotes antitumor activity against prostate cancer via suppressing glycolysis and oxidative phosphorylation. Phytother Res 2023; 37:515-526. [PMID: 36281060 DOI: 10.1002/ptr.7631] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 08/11/2022] [Accepted: 09/03/2022] [Indexed: 11/10/2022]
Abstract
The treatments currently used for prostate cancer (PC) do not meet clinical needs, and thus, new therapies with greater effectiveness are urgently required. Metabolic reprogramming of tumor cells is emerging as an exciting field for cancer therapy. Although the Warburg effect is a common feature of glucose metabolism in many cancers, PC cells have a unique metabolic phenotype. Non-neoplastic prostate cells show reduced oxidative phosphorylation (OXPHOS) because large, accumulated zinc inhibits citrate oxidation. During transformation, there are low levels of zinc in PC cells, and the tricarboxylic acid (TCA) cycle is reactivated. However, metastatic PC exhibits the Warburg effect. Due to metabolic differences in prostate tissue, targeting metabolic alterations in PC cells is an attractive therapeutic strategy. In this study, we investigated the effect of juglone on energy metabolism in PC cells. We found that juglone inhibited cell proliferation and induced apoptosis. Mechanistically, we demonstrated that juglone suppressed OXPHOS and glycolysis due to its inhibition of hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK) activity. Furthermore, downregulation of PFK and PK, but not HK contributed to the inhibition of these enzyme activities. The current study indicates that further development of juglone for PC treatment would be beneficial.
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Affiliation(s)
- Cheng Hu
- College of Laboratory Medicine, Jilin Medical University, Jilin City, Jilin, People's Republic of China
| | - Haiyue Xu
- Clinical Laboratory Department, Changchun Obstetrics and Gynecology Hospital, Changchun city, Jilin, People's Republic of China
| | - Zehao Li
- College of Laboratory Medicine, Jilin Medical University, Jilin City, Jilin, People's Republic of China
| | - Dandan Liu
- College of Laboratory Medicine, Jilin Medical University, Jilin City, Jilin, People's Republic of China
| | - Siqi Zhang
- College of medical technology, Beihua university, Jilin City, Jilin, People's Republic of China
| | - Fang Fang
- College of Laboratory Medicine, Jilin Medical University, Jilin City, Jilin, People's Republic of China
| | - Liguo Wang
- Department of Urology Surgery, Affiliated Hospital of Jilin Medical University, Jilin City, Jilin, People's Republic of China
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14
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Zeković M, Bumbaširević U, Živković M, Pejčić T. Alteration of Lipid Metabolism in Prostate Cancer: Multifaceted Oncologic Implications. Int J Mol Sci 2023; 24:ijms24021391. [PMID: 36674910 PMCID: PMC9863986 DOI: 10.3390/ijms24021391] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/03/2023] [Accepted: 01/04/2023] [Indexed: 01/12/2023] Open
Abstract
Cancer is increasingly recognized as an extraordinarily heterogeneous disease featuring an intricate mutational landscape and vast intra- and intertumor variability on both genetic and phenotypic levels. Prostate cancer (PCa) is the second most prevalent malignant disease among men worldwide. A single metabolic program cannot epitomize the perplexing reprogramming of tumor metabolism needed to sustain the stemness of neoplastic cells and their prominent energy-consuming functional properties, such as intensive proliferation, uncontrolled growth, migration, and invasion. In cancerous tissue, lipids provide the structural integrity of biological membranes, supply energy, influence the regulation of redox homeostasis, contribute to plasticity, angiogenesis and microenvironment reshaping, mediate the modulation of the inflammatory response, and operate as signaling messengers, i.e., lipid mediators affecting myriad processes relevant for the development of the neoplasia. Comprehensive elucidation of the lipid metabolism alterations in PCa, the underlying regulatory mechanisms, and their implications in tumorigenesis and the progression of the disease are gaining growing research interest in the contemporary urologic oncology. Delineation of the unique metabolic signature of the PCa featuring major aberrant pathways including de novo lipogenesis, lipid uptake, storage and compositional reprogramming may provide novel, exciting, and promising avenues for improving diagnosis, risk stratification, and clinical management of such a complex and heterogeneous pathology.
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Affiliation(s)
- Milica Zeković
- Centre of Research Excellence in Nutrition and Metabolism, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
| | - Uros Bumbaširević
- Clinic of Urology, University Clinical Center of Serbia, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Marko Živković
- Clinic of Urology, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Tomislav Pejčić
- Clinic of Urology, University Clinical Center of Serbia, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Correspondence:
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15
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Zhao X, Niu R, Fan S, Jing X, Gao R, Yang H, Wang H, Wang D, Yang Z, Xie Y, She J, Chen P, Meng L. A Dual-Mode NADH Biosensor Based on Gold Nanostars Decorated CoFe 2 Metal-Organic Frameworks to Reveal Dynamics of Cell Metabolism. ACS Sens 2022; 7:2671-2679. [PMID: 36001454 DOI: 10.1021/acssensors.2c01175] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Nicotinamide adenine dinucleotide (NADH) is central to metabolism and implicated in various diseases. Herein, nanohybrids of gold nanostars and metal-organic frameworks are devised and demonstrated as a dual-mode NADH sensor, for which colorimetric detection is enabled by its peroxidase-like nanozyme property and Raman detection is realized by its surface-enhanced Raman scattering property with the detection limit as low as 28 pM. More importantly, this probe enables real-time SERS monitoring in living cells, providing a unique tool to investigate dynamic cellular processes involving NADH. Our experiments reveal that metabolism dynamics is accelerated by glucose and is much higher in cancerous cells. The SERS results can also be verified by the colorimetric detection. This sensor provides a new potential to detect biomarkers and their dynamics in situ.
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Affiliation(s)
- Xiaoping Zhao
- School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry, Xi'an Jiaotong University, Xi'an 710049, China
| | - Ruoxin Niu
- School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry, Xi'an Jiaotong University, Xi'an 710049, China
| | - Shu Fan
- School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry, Xi'an Jiaotong University, Xi'an 710049, China
| | - Xunan Jing
- Talent Highland, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
| | - Rui Gao
- School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry, Xi'an Jiaotong University, Xi'an 710049, China
| | - Hongbo Yang
- School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry, Xi'an Jiaotong University, Xi'an 710049, China
| | - Heng Wang
- School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry, Xi'an Jiaotong University, Xi'an 710049, China
| | - Daquan Wang
- School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry, Xi'an Jiaotong University, Xi'an 710049, China
| | - Zhiwei Yang
- School of Physics, MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, Xi'an Jiaotong University, Xi'an 710049, China
| | - Yunchuan Xie
- School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry, Xi'an Jiaotong University, Xi'an 710049, China
| | - Junjun She
- Talent Highland, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
| | - Peng Chen
- School of Chemistry, Chemical Engineering and Biotechnology, Institute for Digital Molecular Analytics and Science, Nanyang Technological University, 637457, Singapore
| | - Lingjie Meng
- School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry, Xi'an Jiaotong University, Xi'an 710049, China.,Talent Highland, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.,Instrumental Analysis Center of Xi'an Jiaotong University, Xi'an 710049, China
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16
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ACACB is a novel metabolism-related biomarker in the prediction of response to cetuximab therapy inmetastatic colorectal cancer. Acta Biochim Biophys Sin (Shanghai) 2022; 54:1671-1683. [PMID: 36111743 PMCID: PMC9828296 DOI: 10.3724/abbs.2022121] [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] [Indexed: 01/10/2023] Open
Abstract
Cetuximab is one of the most valuable targeted therapy monoclonal antibodies in the treatment of metastatic colorectal cancer (CRC). However, the mechanisms affecting cetuximab resistance in CRC treatment remain unclear. Metabolism, especially fatty acid metabolism, has been reported to play an important role in tumor treatment. The correlation between cetuximab resistance and metabolism and whether it can be a new biomarker to evaluate the sensitivity of cetuximab in CRC treatment still need to be further explored. In this study, we perform a comprehensive analysis to confirm the relationship between fatty acid metabolism and cetuximab resistance, and the differentially expressed genes (DEGs) related to cetuximab drug resistance in CRC are screened by bioinformatics technology. We find that acetyl-CoA carboxylase beta (ACACB), ADH1C, CES1, MGLL, FMO5, and GPT are the hub DEGs, and ACACB is the most important biomarker among them. In addition, we systematically analyze the role of ACACB in the tumorigenesis of CRC, including tissue expression, CRC cell growth, cetuximab sensitivity, and potential downstream pathways, by using bioinformatics techniques, in vitro experiments and clinical cohort validation. Our results confirm that cetuximab resistance is correlated with metabolism. ACACB can lead to decreased sensitivity to cetuximab in CRC, and its mechanism may be related to EGFR phosphorylation, which could affect the activation of the mTOR/Akt signaling pathway and regulation of CDT1-, cyclin D1-, and p21-related cell cycle modulation.
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17
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Amaral A. Energy metabolism in mammalian sperm motility. WIREs Mech Dis 2022; 14:e1569. [DOI: 10.1002/wsbm.1569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/18/2022] [Accepted: 05/21/2022] [Indexed: 11/08/2022]
Affiliation(s)
- Alexandra Amaral
- Department of Developmental Genetics Max Planck Institute for Molecular Genetics Berlin Germany
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18
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Ng RH, Lee JW, Baloni P, Diener C, Heath JR, Su Y. Constraint-Based Reconstruction and Analyses of Metabolic Models: Open-Source Python Tools and Applications to Cancer. Front Oncol 2022; 12:914594. [PMID: 35875150 PMCID: PMC9303011 DOI: 10.3389/fonc.2022.914594] [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: 04/07/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
The influence of metabolism on signaling, epigenetic markers, and transcription is highly complex yet important for understanding cancer physiology. Despite the development of high-resolution multi-omics technologies, it is difficult to infer metabolic activity from these indirect measurements. Fortunately, genome-scale metabolic models and constraint-based modeling provide a systems biology framework to investigate the metabolic states and define the genotype-phenotype associations by integrations of multi-omics data. Constraint-Based Reconstruction and Analysis (COBRA) methods are used to build and simulate metabolic networks using mathematical representations of biochemical reactions, gene-protein reaction associations, and physiological and biochemical constraints. These methods have led to advancements in metabolic reconstruction, network analysis, perturbation studies as well as prediction of metabolic state. Most computational tools for performing these analyses are written for MATLAB, a proprietary software. In order to increase accessibility and handle more complex datasets and models, community efforts have started to develop similar open-source tools in Python. To date there is a comprehensive set of tools in Python to perform various flux analyses and visualizations; however, there are still missing algorithms in some key areas. This review summarizes the availability of Python software for several components of COBRA methods and their applications in cancer metabolism. These tools are evolving rapidly and should offer a readily accessible, versatile way to model the intricacies of cancer metabolism for identifying cancer-specific metabolic features that constitute potential drug targets.
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Affiliation(s)
- Rachel H. Ng
- Institute for Systems Biology, Seattle, WA, United States
- Department of Bioengineering, University of Washington, Seattle, WA, United States
| | - Jihoon W. Lee
- Medical Scientist Training Program, University of Washington, Seattle, WA, United States
- Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | | | | | - James R. Heath
- Institute for Systems Biology, Seattle, WA, United States
- Department of Bioengineering, University of Washington, Seattle, WA, United States
| | - Yapeng Su
- Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
- Herbold Computational Biology Program, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
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19
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ERRγ, a Novel Biomarker, Associates with Pathoglycemia of Endometrial Cancer to Predict Myometrial Invasion. JOURNAL OF ONCOLOGY 2022; 2022:5283388. [PMID: 35774358 PMCID: PMC9239760 DOI: 10.1155/2022/5283388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 04/25/2022] [Accepted: 05/05/2022] [Indexed: 11/18/2022]
Abstract
We aim to investigate the correlation between the expression of estrogen-related receptor γ (ERRγ) and endometrial cancer (EC) progression and to evaluate the potential of ERRγ as a new biomarker for EC diagnosis. We analyzed the ERRγ expression profile and the correlation with the corresponding clinical characteristics of EC samples from The Cancer Genome Atlas (TCGA), the Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases, and the International Cancer Genome Consortium (ICGC) databases. Immunohistochemical (IHC) analysis was conducted on tissue samples, and enzyme linked immunosorbent assay (ELISA) was used in serum samples to detect the levels of ERRγ. The diagnostic performance of ERRγ proteins was assessed using the receiver operating characteristic (ROC). ERRγ showed notably higher expression in EC tissues than in normal endometrium tissues (P < 0.001), which was consistent with the result of TCGA. Overexpression of ERRγ was significantly associated with deep myometrial invasion of EC (P=0.004), and fasting blood glucose (FBG) was higher in EC patients with deep myometrial invasion than in those with superficial myometrial invasion (P=0.040). Further analysis using ELISA showed that the serum ERRγ level was positively correlated with FBG (R = 0.355, P < 0.001). ERRγ is overexpressed in EC and may be involved in regulating glucose metabolism and promoting myometrial invasion of EC. In addition, the area under the ROC curve (AUC) for ERRγ was 0.834, in distinguishing EC patients from healthy individuals, presented 84.0% and 80.0% sensitivity and specificity, respectively, and serum ERRγ has a good diagnostic performance in distinguishing EC patients from healthy people and may be a promising noninvasive biomarker in EC.
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20
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Wang X, Lv Z, Xia H, Guo X, Wang J, Wang J, Liu M. Biochemical recurrence related metabolic novel signature associates with immunity and ADT treatment responses in prostate cancer. Cancer Med 2022; 12:862-878. [PMID: 35681277 PMCID: PMC9844602 DOI: 10.1002/cam4.4856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 05/11/2022] [Accepted: 05/15/2022] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Prostate cancer (PCa) is a unique cancer from a metabolic perspective. Androgen receptor assumes a vital part in normal and malignant prostate cells regarding almost all aspects of cell metabolism, such as glucose, fat, amino acids, nucleotides, and so on. METHODS We used The Cancer Genome Atlas database as training set, Memorial Sloan-Kettering Cancer Center cohort as validation set, and Gene Expression Omnibus database (GSE70769) as test set to identify the optimal prognostic signature. We evaluated the signature in terms of biochemical progression-free survival (bPFS), ROC curve, clinicopathological features, independent prognostic indicators, tumor microenvironment, and infiltrating immune cells. Nomogram was built dependent on the results of cox regression analyses. GSEA algorithm was used to evaluate differences in metabolism. The signature's prediction of androgen deprivation therapy (ADT) response was validated based on two groups of basic cytological experiments treat with ADT (GSE143408 and GSE120343) and the transcriptional information of pre-ADT/post-ADT of six local PCa patients. RESULTS We finally input four screened genes into the stepwise regression model to construct metabolism-related signature. The signature shows good prediction performance in training set, verification set, and test set. A nomogram based on the PSA, Gleason score, T staging, and the signature risk score could predict 1-, 3-, and 5-year bPFS with the high area under curve values. Based on gene-set enrichment analysis, the characteristics of four genes signature could influence some important metabolic biological processes of PCa and were serendipitously found to be significantly related to androgen response. Subsequently, two cytological experimental data sets and our local patient sequencing data set verified that the signature may be helpful to evaluate the therapeutic response of PCa to ADT. CONCLUSIONS Our systematic study definite a metabolism-related gene signature to foresee prognosis of PCa patients which might add to individual prevention and treatment.
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Affiliation(s)
- Xuan Wang
- Department of UrologyBeijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical SciencesBeijingPeople's Republic of China
- Graduate School of Peking Union Medical College and Chinese Academy of Medical SciencesBeijingPeople's Republic of China
| | - Zhengtong Lv
- Department of UrologyBeijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical SciencesBeijingPeople's Republic of China
- Graduate School of Peking Union Medical College and Chinese Academy of Medical SciencesBeijingPeople's Republic of China
| | - Haoran Xia
- Department of UrologyBeijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical SciencesBeijingPeople's Republic of China
- Graduate School of Peking Union Medical College and Chinese Academy of Medical SciencesBeijingPeople's Republic of China
| | - Xiaoxiao Guo
- Department of UrologyBeijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical SciencesBeijingPeople's Republic of China
- Graduate School of Peking Union Medical College and Chinese Academy of Medical SciencesBeijingPeople's Republic of China
| | - Jianye Wang
- Department of UrologyBeijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical SciencesBeijingPeople's Republic of China
- Graduate School of Peking Union Medical College and Chinese Academy of Medical SciencesBeijingPeople's Republic of China
| | - Jianlong Wang
- Department of UrologyBeijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical SciencesBeijingPeople's Republic of China
- Graduate School of Peking Union Medical College and Chinese Academy of Medical SciencesBeijingPeople's Republic of China
| | - Ming Liu
- Department of UrologyBeijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical SciencesBeijingPeople's Republic of China
- Graduate School of Peking Union Medical College and Chinese Academy of Medical SciencesBeijingPeople's Republic of China
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21
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Reyna-Hernández MA, Alarcón-Romero LDC, Ortiz-Ortiz J, Illades-Aguiar B, Jiménez-López MA, Ocampo-Bárcenas A, Morrugares-Ixtepan MO, Torres-Rojas FI. GLUT1, LDHA, and MCT4 Expression Is Deregulated in Cervical Cancer and Precursor Lesions. J Histochem Cytochem 2022; 70:437-446. [PMID: 35615882 PMCID: PMC9169107 DOI: 10.1369/00221554221101662] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/22/2022] [Indexed: 11/22/2022] Open
Abstract
Metabolic reprogramming is typical in cancerous cells and is required for proliferation and cellular survival. In addition, oncoproteins of high-risk human papillomavirus (HR-HPV) are involved in this process. This study evaluated the relationship between glucose transporter I (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter type 4 (MCT4) expression and cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma (ICC) with HR-HPV infection. The protein expression was evaluated in women with CIN I (n=20), CIN II/III (n=16), or ICC (n=24) by immunohistochemistry. The protein expression was analyzed qualitatively by van Zummeren score and quantitatively by Image ProPlus 6 software. LDHA expression increases in HPV-16 infection. In the CIN I group, GLUT1 immunostaining has a 35% protein expression at the membrane level at more than two thirds of the epithelium, which increased by 21.25% more in CIN II/III in more than two thirds of the epithelium. While LDHA and MCT4 in CIN I mostly do not present immunostaining, or this was only limited to the basal stratum, this expression is increased in CIN II/III and ICC cases. The GLUT1, LDHA, and MCT4 expression increased in ICC. The overexpression in high-grade CIN with HR-HPV infection shows a higher risk for cervical carcinoma progression.
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Affiliation(s)
- Ma. A. Reyna-Hernández
- Laboratorio de Citopatología e Histoquímica,
Instituto Estatal de Cancerología “Dr. Arturo Beltrán Ortega,” Acapulco de
Juárez, México
| | - Luz del C. Alarcón-Romero
- Laboratorio de Citopatología e Histoquímica,
Instituto Estatal de Cancerología “Dr. Arturo Beltrán Ortega,” Acapulco de
Juárez, México
| | - Julio Ortiz-Ortiz
- Laboratorio de Biomedicina Molecular, Instituto
Estatal de Cancerología “Dr. Arturo Beltrán Ortega,” Acapulco de Juárez,
México
| | - Berenice Illades-Aguiar
- Laboratorio de Biomedicina Molecular, Instituto
Estatal de Cancerología “Dr. Arturo Beltrán Ortega,” Acapulco de Juárez,
México
| | - Marco A. Jiménez-López
- Facultad de Ciencias Químico-Biológicas,
Universidad Autónoma de Guerrero, Chilpancingo de los Bravo, México, and
Anatomía Patológica, Instituto Estatal de Cancerología “Dr. Arturo Beltrán
Ortega,” Acapulco de Juárez, México
| | - Azucena Ocampo-Bárcenas
- Laboratorio de Patología Molecular, Instituto
Estatal de Cancerología “Dr. Arturo Beltrán Ortega,” Acapulco de Juárez,
México
| | - Martin O. Morrugares-Ixtepan
- Facultad de Ciencias Químico-Biológicas,
Universidad Autónoma de Guerrero, Chilpancingo de los Bravo, México, and
Anatomía Patológica, Instituto Estatal de Cancerología “Dr. Arturo Beltrán
Ortega,” Acapulco de Juárez, México
| | - Francisco I. Torres-Rojas
- Laboratorio de Biomedicina Molecular, Instituto
Estatal de Cancerología “Dr. Arturo Beltrán Ortega,” Acapulco de Juárez,
México
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22
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Liu R, Song Y, Li C, Zhang Z, Xue Z, Huang Q, Yu L, Zhu D, Cao Z, Lu A, Lu C, Liu Y. The naturally-occurring flavonoid nobiletin reverses methotrexate resistance via inhibition of P-glycoprotein synthesis. J Biol Chem 2022; 298:101756. [PMID: 35202652 PMCID: PMC8943250 DOI: 10.1016/j.jbc.2022.101756] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 02/12/2022] [Accepted: 02/14/2022] [Indexed: 12/26/2022] Open
Abstract
Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis (RA). However, after long-term treatment, some patients develop resistance. P-glycoprotein (P-gp), as an indispensable drug transporter, is essential for mediating this MTX resistance. In addition, nobiletin (NOB), a naturally occurring polymethoxylated flavonoid, has also been shown to reverse P-gp–mediated MTX resistance in RA groups; however, the precise role of NOB in this process is still unclear. Here, we administered MTX and NOB alone or in combination to collagen II-induced arthritic (CIA) mice and evaluated disease severity using the arthritis index, synovial histopathological changes, immunohistochemistry, and P-gp expression. In addition, we used conventional RNA-seq to identify targets and possible pathways through which NOB reverses MTX-induced drug resistance. We found that NOB in combination with MTX could enhance its performance in synovial tissue and decrease P-gp expression in CIA mice compared to MTX treatment alone. In vitro, in MTX-resistant fibroblast-like synoviocytes from CIA cells (CIA-FLS/MTX), we show that NOB treatment downregulated the PI3K/AKT/HIF-1α pathway, thereby reducing the synthesis of the P-gp protein. In addition, NOB significantly inhibited glycolysis and metabolic activity of CIA-FLS/MTX cells, which could reduce the production of ATP and block P-gp, ultimately decreasing the efflux of MTX and maintaining its anti-RA effects. In conclusion, this study shows that NOB overcomes MTX resistance in CIA-FLS/MTX cells through the PI3K/AKT/HIF-1α pathway, simultaneously influencing metabolic processes and inhibiting P-gp–induced drug efflux.
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Affiliation(s)
- Rui Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yurong Song
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Chenxi Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Zhengjia Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Zeyu Xue
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Qingcai Huang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Liuchunyang Yu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Dongjie Zhu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Zhiwen Cao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Aiping Lu
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hongkong, China.
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Yuanyan Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China.
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23
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Gautam AK, Kumar P, Raj R, Kumar D, Bhattacharya B, Rajinikanth PS, Chidambaram K, Mahata T, Maity B, Saha S. Preclinical Evaluation of Dimethyl Itaconate Against Hepatocellular Carcinoma via Activation of the e/iNOS-Mediated NF-κB-Dependent Apoptotic Pathway. Front Pharmacol 2022; 12:823285. [PMID: 35095533 PMCID: PMC8795766 DOI: 10.3389/fphar.2021.823285] [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: 11/27/2021] [Accepted: 12/13/2021] [Indexed: 11/30/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common tumors affecting a large population worldwide, with the fifth and seventh greatest mortality rates among men and women, respectively, and the third prime cause of mortality among cancer victims. Dimethyl itaconate (DI) has been reported to be efficacious in colorectal cancer by decreasing IL-1β release from intestinal epithelial cells. In this study, diethylnitrosamine (DEN)-induced HCC in male albino Wistar rats was treated with DI as an anticancer drug. The function and molecular mechanism of DI against HCC in vivo were assessed using histopathology, enzyme-linked immunosorbent assay (ELISA), and Western blot studies. Metabolomics using 1H-NMR was used to investigate metabolic profiles. As per molecular insights, DI has the ability to trigger mitochondrial apoptosis through iNOS- and eNOS-induced activation of the NF-κB/Bcl-2 family of proteins, CytC, caspase-3, and caspase-9 signaling cascade. Serum metabolomics investigations using 1H-NMR revealed that aberrant metabolites in DEN-induced HCC rats were restored to normal following DI therapy. Furthermore, our data revealed that the DI worked as an anti-HCC agent. The anticancer activity of DI was shown to be equivalent to that of the commercial chemotherapeutic drug 5-fluorouracil.
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Affiliation(s)
- Anurag Kumar Gautam
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, India
| | - Pranesh Kumar
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, India.,Department of Pharmacology, Aryakul College of Pharmacy and Research, Lucknow, India
| | - Ritu Raj
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, India
| | - Dinesh Kumar
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, India
| | | | - P S Rajinikanth
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, India
| | - Kumarappan Chidambaram
- Department of Pharmacology and Toxicology, School of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Tarun Mahata
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, India
| | - Biswanath Maity
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, India
| | - Sudipta Saha
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, India
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24
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Protein modifications throughout the lung cancer proteome unravel the cancer-specific regulation of glycolysis. Cell Rep 2021; 37:110137. [PMID: 34936872 DOI: 10.1016/j.celrep.2021.110137] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 06/02/2021] [Accepted: 11/11/2021] [Indexed: 01/16/2023] Open
Abstract
Glycolytic reprogramming is a typical feature of cancer. However, the cancer-specific modulation of glycolytic enzymes requires systematic elucidation. Here, we report a range of dysregulated modifications in association with a family of enzymes specifically related to the glycolysis pathway by systematic identification of delta masses at the proteomic scale in human non-small-cell lung cancer. The most significant modification is the delta mass of 79.967 Da at serine 58 (Ser58) of triosephosphate isomerase (TPI), which is confirmed to be phosphorylation. Blocking TPI Ser58 phosphorylation dramatically inhibits glycolysis, cancer growth, and metastasis. The protein kinase PRKACA directly phosphorylates TPI Ser58, thereby enhancing TPI enzymatic activity and glycolysis. The upregulation of TPI Ser58 phosphorylation is detected in various human tumor specimens and correlates with poor survival. Therefore, our study identifies a number of cancer-specific protein modifications spanned on glycolytic enzymes and unravels the significance of TPI Ser58 phosphorylation in glycolysis and lung cancer development.
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25
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Zheng S, Song Q, Zhang P. Metabolic Modifications, Inflammation, and Cancer Immunotherapy. Front Oncol 2021; 11:703681. [PMID: 34631531 PMCID: PMC8497755 DOI: 10.3389/fonc.2021.703681] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 08/20/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer immunotherapy has accomplished significant progresses on treatment of various cancers in the past decade; however, recent studies revealed more and more heterogeneity in tumor microenvironment which cause unneglectable therapy resistance. A central phenomenon in tumor malignancy is metabolic dysfunctionality; it reprograms metabolic homeostasis in tumor and stromal cells thus affecting metabolic modifications on specific proteins. These posttranslational modifications include glycosylation and palmitoylation, which usually alter the protein localization, stability, and function. Many of these proteins participate in acute or chronic inflammation and play critical roles in tumorigenesis and progression. Therefore, targeting these metabolic modifications in immune checkpoints and inflammation provides an attractive therapeutic strategy for certain cancers. In this review, we summarize the recent progresses on metabolic modifications in this field, focus on the mechanisms on how glycosylation and palmitoylation regulate innate immune and inflammation, and we further discuss designing new immunotherapy targeting metabolic modifications. We aim to improve immunotherapy or targeted-therapy response and achieve more accurate individual therapy.
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Affiliation(s)
- Sihao Zheng
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qibin Song
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Pingfeng Zhang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
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26
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Hu Y, Mu H, Deng Z. The transcription factor TEAD4 enhances lung adenocarcinoma progression through enhancing PKM2 mediated glycolysis. Cell Biol Int 2021; 45:2063-2073. [PMID: 34196069 DOI: 10.1002/cbin.11654] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 04/20/2021] [Accepted: 06/16/2021] [Indexed: 01/24/2023]
Abstract
Lung adenocarcinoma (LUAD) is a deadly disease with a hallmark of aberrant metabolism. TEA domain 4 (TEAD4) is involved in the progression of several forms of cancer including LUAD. However, the role of TEAD4 in LUAD glucose metabolism is rarely reported as well as its potential mechanisms. Pyruvate kinase isozymes M2 (PKM2), the key regulatory enzymes in glycolysis, was predicted to be a target for TEAD4 by bioinformatics analysis. Thus, we aimed to explore whether TEAD4/PKM2 axis was related to LUAD glucose metabolism and malignant phenotype. The expression level of TEAD4 and PKM2 was measured by quantitative real-time PCR and Western blot. Luciferase reporter assay were employed to verify the effect of TEAD4 on PKM2 promoter as well as TEAD4/PKM2 axis on reporter activity of hypoxia inducible factor-1α (HIF-1α). Glycolysis was investigated according to glucose consumption, lactate production and the extracellular acidification rate. The present study indicated that TEAD4 and PKM2 were upregulated in LUAD and closely related to prognosis. Mechanistic investigations identified that TEAD4 played a key role as a transcription factor and promoted PKM2 transcription and expression, which further altered the reporter activity of HIF-1α and upregulated HIF-1α-targeted glycolytic genes glucose transporter-1 and hexokinase II. Functional assays revealed that TEAD4 and PKM2 affected glycolytic and 2-DG blocked the positive function of TEAD4 and PKM2 on glycolytic. Besides, TEAD4/PKM2 axis affects LUAD cell viability, apoptosis, migration, and invasion. Together, these data provided evidence that both TEAD4 and PKM2 were poor prognosticator. Targeting TEAD4/PKM2 axis might be an effective therapeutic strategy for LUAD.
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Affiliation(s)
- Yan Hu
- Department of Respiratory, The First People's Hospital of Zigong City, Zigong, Sichuan, China
| | - Hanshuo Mu
- Department of Clinical Medicine, Nantong University, Nantong, Jiangsu, China
| | - Zhiping Deng
- Department of Respiratory, The First People's Hospital of Zigong City, Zigong, Sichuan, China
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27
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Frades I, Foguet C, Cascante M, Araúzo-Bravo MJ. Genome Scale Modeling to Study the Metabolic Competition between Cells in the Tumor Microenvironment. Cancers (Basel) 2021; 13:4609. [PMID: 34572839 PMCID: PMC8470216 DOI: 10.3390/cancers13184609] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/06/2021] [Accepted: 09/09/2021] [Indexed: 12/31/2022] Open
Abstract
The tumor's physiology emerges from the dynamic interplay of numerous cell types, such as cancer cells, immune cells and stromal cells, within the tumor microenvironment. Immune and cancer cells compete for nutrients within the tumor microenvironment, leading to a metabolic battle between these cell populations. Tumor cells can reprogram their metabolism to meet the high demand of building blocks and ATP for proliferation, and to gain an advantage over the action of immune cells. The study of the metabolic reprogramming mechanisms underlying cancer requires the quantification of metabolic fluxes which can be estimated at the genome-scale with constraint-based or kinetic modeling. Constraint-based models use a set of linear constraints to simulate steady-state metabolic fluxes, whereas kinetic models can simulate both the transient behavior and steady-state values of cellular fluxes and concentrations. The integration of cell- or tissue-specific data enables the construction of context-specific models that reflect cell-type- or tissue-specific metabolic properties. While the available modeling frameworks enable limited modeling of the metabolic crosstalk between tumor and immune cells in the tumor stroma, future developments will likely involve new hybrid kinetic/stoichiometric formulations.
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Affiliation(s)
- Itziar Frades
- Computational Biology and Systems Biomedicine Group, Biodonostia Health Research Institute, 20009 San Sebastian, Spain;
| | - Carles Foguet
- Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of University of Barcelona, Faculty of Biology, Universitat de Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain; (C.F.); (M.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD) (CB17/04/00023) and Metabolomics Node at Spanish National Bioinformatics Institute (INB-ISCIII-ES-ELIXIR), Instituto de Salud Carlos III (ISCIII), 28020 Madrid, Spain
| | - Marta Cascante
- Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of University of Barcelona, Faculty of Biology, Universitat de Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain; (C.F.); (M.C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD) (CB17/04/00023) and Metabolomics Node at Spanish National Bioinformatics Institute (INB-ISCIII-ES-ELIXIR), Instituto de Salud Carlos III (ISCIII), 28020 Madrid, Spain
| | - Marcos J. Araúzo-Bravo
- Computational Biology and Systems Biomedicine Group, Biodonostia Health Research Institute, 20009 San Sebastian, Spain;
- Max Planck Institute of Molecular Biomedicine, 48167 Münster, Germany
- Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERfes), 28015 Madrid, Spain
- Translational Bioinformatics Network (TransBioNet), 8001 Barcelona, Spain
- Ikerbasque, Basque Foundation for Science, 48012 Bilbao, Spain
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28
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Guo E, Guo L, An C, Zhang C, Song K, Wang G, Duan C, Zhang X, Yang X, Yuan Z, Guo J, Sun J, Meng H, Chang R, Li X, Xiu C, Mao X, Miao S. Prognostic Significance of Lactate Dehydrogenase in Patients Undergoing Surgical Resection for Laryngeal Squamous Cell Carcinoma. Cancer Control 2021; 27:1073274820978795. [PMID: 33297727 PMCID: PMC8480349 DOI: 10.1177/1073274820978795] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
The aim is to estimate the prognostic value of lactate dehydrogenase (LDH) in patients undergoing surgical resection for laryngeal squamous cell carcinoma (LSCC). A total of 640 resected LSCC patients were included. Preoperative lactate dehydrogenase (LDH) was assessed. Kaplan-Meier survival analysis and Cox regression analysis were conducted for overall survival (OS) and recurrence-free survival (RFS). Kaplan-Meier analysis, univariate analysis and multivariate analysis demonstrated significant prognostic value for preoperative LDH. Although LDH was predictor of OS, it failed to be a predictor of RFS. The univariate HR and 95% CI of LDH were 0.484 and 0.357-0.658 (P < 0.0001). The multivariate analysis showed that LDH (HR = 0.518, 95% CI: 0.380-0.705, p < 0.0001) was related to OS. Elevated preoperative LDH >132 IU/L was significantly associated with better survival. Preoperative LDH might be an independent prognostic marker of OS in LSCC patients undergoing surgical resection.
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Affiliation(s)
- Erliang Guo
- Department of Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150081, China.,* These two authors have contributed equally to the work
| | - Lunhua Guo
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, China.,* These two authors have contributed equally to the work
| | - Changming An
- Department of Head and Neck Surgery, Chinese National Cancer Center & Chinese Academy of Medical Sciences Cancer Hospital. Beijing 100000, China
| | - Cong Zhang
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Kaibin Song
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Guohui Wang
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Chunbin Duan
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Xiwei Zhang
- Department of Head and Neck Surgery, Chinese National Cancer Center & Chinese Academy of Medical Sciences Cancer Hospital. Beijing 100000, China
| | - Xianguang Yang
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Zhennan Yuan
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Junnan Guo
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Ji Sun
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Hongxue Meng
- Department of Pathology, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Rui Chang
- Department of Head and Neck Surgery, Anyang Cancer Hospital, Anyang 455000, China
| | - Xiaomei Li
- Department of Pathology, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Cheng Xiu
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Xionghui Mao
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Susheng Miao
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, China
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29
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Wang YT, Lin MR, Chen WC, Wu WH, Wang FS. Optimization of a modeling platform to predict oncogenes from genome-scale metabolic networks of non-small-cell lung cancers. FEBS Open Bio 2021. [PMID: 34137202 PMCID: PMC8329960 DOI: 10.1002/2211-5463.13231] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/19/2021] [Accepted: 06/16/2021] [Indexed: 12/25/2022] Open
Abstract
Cancer cell dysregulations result in the abnormal regulation of cellular metabolic pathways. By simulating this metabolic reprogramming using constraint-based modeling approaches, oncogenes can be predicted, and this knowledge can be used in prognosis and treatment. We introduced a trilevel optimization problem describing metabolic reprogramming for inferring oncogenes. First, this study used RNA-Seq expression data of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) samples and their healthy counterparts to reconstruct tissue-specific genome-scale metabolic models and subsequently build the flux distribution pattern that provided a measure for the oncogene inference optimization problem for determining tumorigenesis. The platform detected 45 genes for LUAD and 84 genes for LUSC that lead to tumorigenesis. A high level of differentially expressed genes was not an essential factor for determining tumorigenesis. The platform indicated that pyruvate kinase (PKM), a well-known oncogene with a low level of differential gene expression in LUAD and LUSC, had the highest fitness among the predicted oncogenes based on computation. By contrast, pyruvate kinase L/R (PKLR), an isozyme of PKM, had a high level of differential gene expression in both cancers. Phosphatidylserine synthase 1 (PTDSS1), an oncogene in LUAD, was inferred to have a low level of differential gene expression, and overexpression could significantly reduce survival probability. According to the factor analysis, PTDSS1 characteristics were close to those of the template, but they were unobvious in LUSC. Angiotensin-converting enzyme 2 (ACE2) has recently garnered widespread interest as the SARS-CoV-2 virus receptor. Moreover, we determined that ACE2 is an oncogene of LUSC but not of LUAD. The platform developed in this study can identify oncogenes with low levels of differential expression and be used to identify potential therapeutic targets for cancer treatment.
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Affiliation(s)
- You-Tyun Wang
- Department of Chemical Engineering, National Chung Cheng University, Chiayi, Taiwan
| | - Min-Ru Lin
- Department of Chemical Engineering, National Chung Cheng University, Chiayi, Taiwan
| | - Wei-Chen Chen
- Department of Chemical Engineering, National Chung Cheng University, Chiayi, Taiwan
| | - Wu-Hsiung Wu
- Department of Chemical Engineering, National Chung Cheng University, Chiayi, Taiwan
| | - Feng-Sheng Wang
- Department of Chemical Engineering, National Chung Cheng University, Chiayi, Taiwan
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30
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Exploring the Metabolic Heterogeneity of Cancers: A Benchmark Study of Context-Specific Models. J Pers Med 2021; 11:jpm11060496. [PMID: 34205912 PMCID: PMC8229374 DOI: 10.3390/jpm11060496] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 05/25/2021] [Accepted: 05/28/2021] [Indexed: 12/18/2022] Open
Abstract
Metabolic heterogeneity is a hallmark of cancer and can distinguish a normal phenotype from a cancer phenotype. In the systems biology domain, context-specific models facilitate extracting physiologically relevant information from high-quality data. Here, to utilize the heterogeneity of metabolic patterns to discover biomarkers of all cancers, we benchmarked thousands of context-specific models using well-established algorithms for the integration of omics data into the generic human metabolic model Recon3D. By analyzing the active reactions capable of carrying flux and their magnitude through flux balance analysis, we proved that the metabolic pattern of each cancer is unique and could act as a cancer metabolic fingerprint. Subsequently, we searched for proper feature selection methods to cluster the flux states characterizing each cancer. We employed PCA-based dimensionality reduction and a random forest learning algorithm to reveal reactions containing the most relevant information in order to effectively identify the most influential fluxes. Conclusively, we discovered different pathways that are probably the main sources for metabolic heterogeneity in cancers. We designed the GEMbench website to interactively present the data, methods, and analysis results.
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31
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Wang G, Liu X, Wang D, Sun M, Yang Q. Identification and Development of Subtypes With Poor Prognosis in Pan-Gynecological Cancer Based on Gene Expression in the Glycolysis-Cholesterol Synthesis Axis. Front Oncol 2021; 11:636565. [PMID: 33842342 PMCID: PMC8025671 DOI: 10.3389/fonc.2021.636565] [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: 12/01/2020] [Accepted: 02/19/2021] [Indexed: 12/24/2022] Open
Abstract
Objective: Metabolic reprogramming is an important biomarker of cancer. Metabolic adaptation driven by oncogenes allows tumor cells to survive and grow in a complex tumor microenvironment. The heterogeneity of tumor metabolism is related to survival time, somatic cell-driven gene mutations, and tumor subtypes. Using the heterogeneity of different metabolic pathways for the classification of gynecological pan-cancer is of great significance for clinical decision-making and prognosis prediction. Methods: RNA sequencing data for patients with ovarian, cervical, and endometrial cancer were downloaded from The Cancer Genome Atlas database. Genes related to glycolysis and cholesterol were extracted and clustered coherently by using ConsensusClusterPlus. The mutations and copy number variations in different subtypes were compared, and the immune scores of the samples were evaluated. The limma R package was used to identify differentially expressed genes between subtypes, and the WebGestaltR package (V0.4.2) was used to conduct Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology functional enrichment analyses. A risk score model was constructed based on multivariate Cox analysis. Prognostic classification efficiency was analyzed by using timeROC, and internal and external cohorts were used to verify the robustness of the model. Results: Based on the expression of 11 glycolysis-related genes and seven cholesterol-related genes, 1,204 samples were divided into four metabolic subtypes (quiescent, glycolysis, cholesterol, and mixed). Immune infiltration scores showed significant differences among the four subtypes. Survival analysis showed that the prognosis of the cholesterol subtype was better than that of the quiescent subtype. A nine-gene signature was constructed based on differentially expressed genes between the cholesterol and quiescent subtypes, and it was validated by using an independent cohort of the International Cancer Genome Consortium. Compared with existing models, our nine-gene signature had good prediction performance. Conclusion: The metabolic classification of gynecological pan-cancer based on metabolic reprogramming may provide an important basis for clinicians to choose treatment options, predict treatment resistance, and predict patients' clinical outcomes.
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Affiliation(s)
- Guangwei Wang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaofei Liu
- Department of Obstetrics and Gynecology, Shenyang Women's and Children's Hospital, Shenyang, China
| | - Dandan Wang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Meige Sun
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qing Yang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
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32
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Yang Y, Liu L, Sun J, Wang S, Yang Z, Li H, Huang N, Zhao W. Deoxypodophyllotoxin Inhibits Non-Small Cell Lung Cancer Cell Growth by Reducing HIF-1α-Mediated Glycolysis. Front Oncol 2021; 11:629543. [PMID: 33732648 PMCID: PMC7959795 DOI: 10.3389/fonc.2021.629543] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 01/11/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer cell proliferation is a metabolically demanding process that requires high rate of glycolysis to support anabolic growth. Deoxypodophyllotoxin (DPT) is a natural flavonolignan with various pharmacological activities, including antitumor effect. However, whether DPT affects the metabolic reprogramming of cancer cells is unknown. The purpose of this study is to investigate the role of DPT on non-small cell lung cancer (NSCLC) and to explore whether HIF-1α-mediated glycolysis is involved in its mechanism of action.The level of HIF-1α mRNA and protein in NSCLC cells following DPT treatment was detected using qRT-PCR and western blotting, respectively. Cell Counting Kit-8 (CCK-8) and caspase-3 activity assays were performed to analyze cell proliferation and apoptosis. The underlying molecular mechanism was identified by dual luciferase assay, Western blotting, qRT-PCR, glucose consumption, lactate production, and immunoprecipitation. A murine NSCLC model was used to clarify the effect of DPT treatment on tumor cell proliferation. Our findings showed that DPT treatment inhibited NSCLC cell growth in a dose- and time-dependent manner. Further analysis suggested that DPT treatment inhibited HIF-1α signaling pathway by Parkin-mediated protein degradation in NSCLC cells. DPT treatment significantly decreased glucose consumption and lactate production. In addition, DPT treatment reduced the expression of HIF-1α target genes, including GLUT1, HK2 and LDHA, resulting in reduction in glycolysis. We further revealed that DPT-induced cell growth inhibition and increased glucose and lactate levels could be reversed by overexpressing HIF-1α. Additionally, we found that DPT repressed NSCLC growth and GLUT1, HK2 and LDHA expression in vivo. Overall, this study suggested that DPT inhibited NSCLC growth by preventing HIF-1α-mediated glycolysis.
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Affiliation(s)
- Yuping Yang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Lingling Liu
- School of Laboratory Medicine/Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-origin Food, Chengdu Medical College, Chengdu, China
- Development and Regeneration Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu, China
| | - Jinghui Sun
- School of Laboratory Medicine/Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-origin Food, Chengdu Medical College, Chengdu, China
| | - Shu Wang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China
| | | | - Honghui Li
- Department of Refractive Surgery, Chengdu Aier Eye Hospital, Chengdu, China
| | - Na Huang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Wei Zhao
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
- School of Laboratory Medicine/Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-origin Food, Chengdu Medical College, Chengdu, China
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Tu MJ, Duan Z, Liu Z, Zhang C, Bold RJ, Gonzalez FJ, Kim EJ, Yu AM. MicroRNA-1291-5p Sensitizes Pancreatic Carcinoma Cells to Arginine Deprivation and Chemotherapy through the Regulation of Arginolysis and Glycolysis. Mol Pharmacol 2020; 98:686-694. [PMID: 33051382 PMCID: PMC7673485 DOI: 10.1124/molpharm.120.000130] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 09/17/2020] [Indexed: 12/12/2022] Open
Abstract
Cancer cells are dysregulated and addicted to continuous supply and metabolism of nutritional glucose and amino acids (e.g., arginine) to drive the synthesis of critical macromolecules for uncontrolled growth. Recent studies have revealed that genome-derived microRNA (miRNA or miR)-1291-5p (miR-1291-5p or miR-1291) may modulate the expression of argininosuccinate synthase (ASS1) and glucose transporter protein type 1 (GLUT1). We also developed a novel approach to produce recombinant miR-1291 agents for research, which are distinguished from conventional chemo-engineered miRNA mimics. Herein, we firstly demonstrated that bioengineered miR-1291 agent was selectively processed to high levels of target miR-1291-5p in human pancreatic cancer (PC) cells. After the suppression of ASS1 protein levels, miR-1291 perturbed arginine homeostasis and preferably sensitized ASS1-abundant L3.3 cells to arginine deprivation therapy. In addition, miR-1291 treatment reduced the protein levels of GLUT1 in both AsPC-1 and PANC-1 cells, leading to a lower glucose uptake (deceased > 40%) and glycolysis capacity (reduced approximately 50%). As a result, miR-1291 largely improved cisplatin efficacy in the inhibition of PC cell viability. Our results demonstrated that miR-1291 was effective to sensitize PC cells to arginine deprivation treatment and chemotherapy through targeting ASS1- and GLUT1-mediated arginolysis and glycolysis, respectively, which may provide insights into understanding miRNA signaling underlying cancer cell metabolism and development of new strategies for the treatment of lethal PC. SIGNIFICANCE STATEMENT: Many anticancer drugs in clinical use and under investigation exert pharmacological effects or improve efficacy of coadministered medications by targeting cancer cell metabolism. Using new recombinant miR-1291 agent, we revealed that miR-1291 acts as a metabolism modulator in pancreatic carcinoma cells through the regulation of argininosuccinate synthase- and glucose transporter protein type 1-mediated arginolysis and glycolysis. Consequently, miR-1291 effectively enhanced the efficacy of arginine deprivation (pegylated arginine deiminase) and chemotherapy (cisplatin), offering new insights into development of rational combination therapies.
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Affiliation(s)
- Mei-Juan Tu
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Zhijian Duan
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Zhenzhen Liu
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Chao Zhang
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Richard J Bold
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Frank J Gonzalez
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Edward J Kim
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Ai-Ming Yu
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
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34
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Altered Levels of Desaturation and ω-6 Fatty Acids in Breast Cancer Patients' Red Blood Cell Membranes. Metabolites 2020; 10:metabo10110469. [PMID: 33212920 PMCID: PMC7698438 DOI: 10.3390/metabo10110469] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 11/06/2020] [Accepted: 11/12/2020] [Indexed: 02/07/2023] Open
Abstract
Red blood cell (RBC) membrane can reflect fatty acid (FA) contribution from diet and biosynthesis. In cancer, membrane FAs are involved in tumorigenesis and invasiveness, and are indicated as biomarkers to monitor the disease evolution as well as potential targets for therapies and nutritional strategies. The present study provides RBC membrane FA profiles in recently diagnosed breast cancer patients before starting chemotherapy treatment. Patients and controls were recruited, and their dietary habits were collected. FA lipidomic analysis of mature erythrocyte membrane phospholipids in blood samples was performed. Data were adjusted to correct for the effects of diet, body mass index (BMI), and age, revealing that patients showed lower levels of saturated fatty acids (SFA) and higher levels of monounsaturated fatty acid, cis-vaccenic (25%) than controls, with consequent differences in desaturase enzymatic index (∆9 desaturase, -13.1%). In the case of polyunsaturated fatty acids (PUFA), patients had higher values of ω-6 FA (C18:2 (+11.1%); C20:4 (+7.4%)). RBC membrane lipidomic analysis in breast cancer revealed that ω-6 pathways are favored. These results suggest new potential targets for treatments and better nutritional guidelines.
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35
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Host and Bacterial Glycolysis during Chlamydia trachomatis Infection. Infect Immun 2020; 88:IAI.00545-20. [PMID: 32900818 DOI: 10.1128/iai.00545-20] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 09/02/2020] [Indexed: 12/14/2022] Open
Abstract
The obligate intracellular pathogen Chlamydia trachomatis is the leading cause of noncongenital blindness and causative agent of the most common sexually transmitted infection of bacterial origin. With a reduced genome, C. trachomatis is dependent on its host for survival, in part due to a need for the host cell to compensate for incomplete bacterial metabolic pathways. However, relatively little is known regarding how C. trachomatis is able to hijack host cell metabolism. In this study, we show that two host glycolytic enzymes, aldolase A and pyruvate kinase, as well as lactate dehydrogenase, are enriched at the C. trachomatis inclusion membrane during infection. Inclusion localization was not species specific, since a similar phenotype was observed with C. muridarum Time course experiments showed that the number of positive inclusions increased throughout the developmental cycle. In addition, these host enzymes colocalized to the same inclusion, and their localization did not appear to be dependent on sustained bacterial protein synthesis or on intact host actin, vesicular trafficking, or microtubules. Depletion of the host glycolytic enzyme aldolase A resulted in decreased inclusion size and infectious progeny production, indicating a role for host glycolysis in bacterial growth. Finally, quantitative PCR analysis showed that expression of C. trachomatis glycolytic enzymes inversely correlated with host enzyme localization at the inclusion. We discuss potential mechanisms leading to inclusion localization of host glycolytic enzymes and how it could benefit the bacteria. Altogether, our findings provide further insight into the intricate relationship between host and bacterial metabolism during Chlamydia infection.
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36
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Carpenter RL, Gökmen-Polar Y. HSF1 as a Cancer Biomarker and Therapeutic Target. Curr Cancer Drug Targets 2020; 19:515-524. [PMID: 30338738 DOI: 10.2174/1568009618666181018162117] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 07/30/2018] [Accepted: 09/15/2018] [Indexed: 12/30/2022]
Abstract
Heat shock factor 1 (HSF1) was discovered in 1984 as the master regulator of the heat shock response. In this classical role, HSF1 is activated following cellular stresses such as heat shock that ultimately lead to HSF1-mediated expression of heat shock proteins to protect the proteome and survive these acute stresses. However, it is now becoming clear that HSF1 also plays a significant role in several diseases, perhaps none more prominent than cancer. HSF1 appears to have a pleiotropic role in cancer by supporting multiple facets of malignancy including migration, invasion, proliferation, and cancer cell metabolism among others. Because of these functions, and others, of HSF1, it has been investigated as a biomarker for patient outcomes in multiple cancer types. HSF1 expression alone was predictive for patient outcomes in multiple cancer types but in other instances, markers for HSF1 activity were more predictive. Clearly, further work is needed to tease out which markers are most representative of the tumor promoting effects of HSF1. Additionally, there have been several attempts at developing small molecule inhibitors to reduce HSF1 activity. All of these HSF1 inhibitors are still in preclinical models but have shown varying levels of efficacy at suppressing tumor growth. The growth of research related to HSF1 in cancer has been enormous over the last decade with many new functions of HSF1 discovered along the way. In order for these discoveries to reach clinical impact, further development of HSF1 as a biomarker or therapeutic target needs to be continued.
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Affiliation(s)
- Richard L Carpenter
- Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Bloomington, IN 47405, United States.,Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Bloomington, IN 47405, United States.,Department of Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405, United States
| | - Yesim Gökmen-Polar
- Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Bloomington, IN 47405, United States.,Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
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37
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Ferreri C, Sansone A, Ferreri R, Amézaga J, Tueros I. Fatty Acids and Membrane Lipidomics in Oncology: A Cross-Road of Nutritional, Signaling and Metabolic Pathways. Metabolites 2020; 10:metabo10090345. [PMID: 32854444 PMCID: PMC7570129 DOI: 10.3390/metabo10090345] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 08/20/2020] [Accepted: 08/23/2020] [Indexed: 12/11/2022] Open
Abstract
Fatty acids are closely involved in lipid synthesis and metabolism in cancer. Their amount and composition are dependent on dietary supply and tumor microenviroment. Research in this subject highlighted the crucial event of membrane formation, which is regulated by the fatty acids' molecular properties. The growing understanding of the pathways that create the fatty acid pool needed for cell replication is the result of lipidomics studies, also envisaging novel fatty acid biosynthesis and fatty acid-mediated signaling. Fatty acid-driven mechanisms and biological effects in cancer onset, growth and metastasis have been elucidated, recognizing the importance of polyunsaturated molecules and the balance between omega-6 and omega-3 families. Saturated and monounsaturated fatty acids are biomarkers in several types of cancer, and their characterization in cell membranes and exosomes is under development for diagnostic purposes. Desaturase enzymatic activity with unprecedented de novo polyunsaturated fatty acid (PUFA) synthesis is considered the recent breakthrough in this scenario. Together with the link between obesity and cancer, fatty acids open interesting perspectives for biomarker discovery and nutritional strategies to control cancer, also in combination with therapies. All these subjects are described using an integrated approach taking into account biochemical, biological and analytical aspects, delineating innovations in cancer prevention, diagnostics and treatments.
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Affiliation(s)
- Carla Ferreri
- Istituto per la Sintesi Organica e la Fotoreattività, Consiglio Nazionale delle Ricerche, Via Piero Gobetti 101, 40129 Bologna, Italy;
- Correspondence:
| | - Anna Sansone
- Istituto per la Sintesi Organica e la Fotoreattività, Consiglio Nazionale delle Ricerche, Via Piero Gobetti 101, 40129 Bologna, Italy;
| | - Rosaria Ferreri
- Department of Integrated Medicine, Tuscany Reference Centre for Integrated Medicine in the hospital pathway, Pitigliano Hospital, Via Nicola Ciacci, 340, 58017 Pitigliano, Italy;
| | - Javier Amézaga
- AZTI, Food and Health, Parque Tecnológico de Bizkaia, Astondo Bidea, Edificio 609, 48160 Derio, Spain; (J.A.); (I.T.)
| | - Itziar Tueros
- AZTI, Food and Health, Parque Tecnológico de Bizkaia, Astondo Bidea, Edificio 609, 48160 Derio, Spain; (J.A.); (I.T.)
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38
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Wu Q, Ba-Alawi W, Deblois G, Cruickshank J, Duan S, Lima-Fernandes E, Haight J, Tonekaboni SAM, Fortier AM, Kuasne H, McKee TD, Mahmoud H, Kushida M, Cameron S, Dogan-Artun N, Chen W, Nie Y, Zhang LX, Vellanki RN, Zhou S, Prinos P, Wouters BG, Dirks PB, Done SJ, Park M, Cescon DW, Haibe-Kains B, Lupien M, Arrowsmith CH. GLUT1 inhibition blocks growth of RB1-positive triple negative breast cancer. Nat Commun 2020; 11:4205. [PMID: 32826891 PMCID: PMC7442809 DOI: 10.1038/s41467-020-18020-8] [Citation(s) in RCA: 167] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 07/28/2020] [Indexed: 12/20/2022] Open
Abstract
Triple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1) and associated metabolic dependencies in TNBC, we investigated the vulnerability of TNBC cell lines and patient-derived samples to GLUT1 inhibition. We report that genetic or pharmacological inhibition of GLUT1 with BAY-876 impairs the growth of a subset of TNBC cells displaying high glycolytic and lower oxidative phosphorylation (OXPHOS) rates. Pathway enrichment analysis of gene expression data suggests that the functionality of the E2F pathway may reflect to some extent OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) strongly correlate with the degree of sensitivity to GLUT1 inhibition in TNBC, where RB1-negative cells are insensitive to GLUT1 inhibition. Collectively, our results highlight a strong and targetable RB1-GLUT1 metabolic axis in TNBC and warrant clinical evaluation of GLUT1 inhibition in TNBC patients stratified according to RB1 protein expression levels.
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Affiliation(s)
- Qin Wu
- Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada
| | - Wail Ba-Alawi
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada
| | - Genevieve Deblois
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada
| | - Jennifer Cruickshank
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada
| | - Shili Duan
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada
| | - Evelyne Lima-Fernandes
- Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada
| | - Jillian Haight
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada
| | - Seyed Ali Madani Tonekaboni
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada
| | - Anne-Marie Fortier
- Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada
| | - Hellen Kuasne
- Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada
| | - Trevor D McKee
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada
- Princess Margaret Cancer Centre, STTARR Innovation Facility, Toronto, ON, Canada
| | - Hassan Mahmoud
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada
- Faculty of Computer and Informatics, Benha University, Benha, Egypt
| | - Michelle Kushida
- Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain tumor Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
| | - Sarina Cameron
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada
| | - Nergiz Dogan-Artun
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada
| | - WenJun Chen
- Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada
| | - Yan Nie
- Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada
| | - Lan Xin Zhang
- Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada
| | - Ravi N Vellanki
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada
| | - Stanley Zhou
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada
| | - Panagiotis Prinos
- Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada
| | - Bradly G Wouters
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada
| | - Peter B Dirks
- Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain tumor Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
- Division of Neurosurgery, University of Toronto, Toronto, ON, M5S 1A8, Canada
- Departments of Molecular Genetics and Surgery, University of Toronto, Toronto, ON, M5S1A8, Canada
| | - Susan J Done
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada
| | - Morag Park
- Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada
| | - David W Cescon
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada
| | - Benjamin Haibe-Kains
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada
- Department of Computer Science, University of Toronto, Toronto, M5T 3A1, ON, Canada
- Ontario Institue for Cancer Research, Toronto, M5G 2M9, ON, Canada
- Vector Institute for Artificial Intelligence, Toronto, ON, Canada
| | - Mathieu Lupien
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada.
- Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada.
- Ontario Institue for Cancer Research, Toronto, M5G 2M9, ON, Canada.
| | - Cheryl H Arrowsmith
- Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
- Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada.
- Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada.
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39
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Liu J, Yang Q, Sun H, Wang X, Saiyin H, Zhang H. The circ-AMOTL1/ENO1 Axis Implicated in the Tumorigenesis of OLP-Associated Oral Squamous Cell Carcinoma. Cancer Manag Res 2020; 12:7219-7230. [PMID: 32884340 PMCID: PMC7440838 DOI: 10.2147/cmar.s251348] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 07/10/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Oral squamous cell carcinoma (OSCC) may develop from a variety of oral potentially malignant disorders, but the mechanism of malignant transformation is still unknown. Among them, oral lichen planus (OLP) has a high prevalence. Previous studies have shown that α-enolase (ENO1) can promote cell proliferation and play an important role in tumorigenesis. In this study, we aim to explore the mechanism of ENO1 regulation in the process of OSCC tumorigenesis from OLP. METHODS ENO1 expression in tissues was determined by real-time quantitative PCR and immunohistochemistry. ENO1 was knocked down in cal-27 to observe the change in cell proliferation. Then, RNA-seq and bioinformatics analyses were conducted between OLP and OSCC samples. The expression of circ-AMOTL1, miRNA-22-3p, and miRNA-1294 was assessed using the real-time quantitative PCR. With knockdown and overexpression of circ-AMOTL1 in vitro, the change of ENO1 in the mRNA level was also assessed. RESULTS ENO1 was enhanced in the OSCC samples in comparison with OLP. Immunohistochemistry and real-time quantitative PCR results showed that ENO1 was significantly higher in OSCC tissue than in the OLP group, with a statistically significant difference (p<0.05). When ENO1 was knocked down in cal-27, cell proliferation was inhibited (p<0.05). The expression of miR-22-3p and miR-1294 was decreased in OSCC tissues, whereas ENO1 and circ-AMOTL1 increased. In an in vitro study, knockdown of circ-AMOTL1 resulted in a decrease of ENO1, while overexpression of circ-AMOTL1 led to an increase of ENO1 in the mRNA level. CONCLUSION We confirmed that ENO1 expression was elevated in OSCC and increased cell proliferation. In an in vitro study, ENO1 expression was promoted by circ-AMOTL1. ENO1 may play a role as a tumor-promoting gene in OSCC through the circ-AMOTL1/miR-22-3p/miR-1294 network. These novel findings may shed further light on the pathogenesis from OLP to OSCC and the potential precursor markers.
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Affiliation(s)
- Jin Liu
- Department of Stomatology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Qiaozhen Yang
- Department of Stomatology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Hongying Sun
- Department of Stomatology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Xiaxia Wang
- Department of Stomatology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Hexige Saiyin
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, People’s Republic of China
| | - Hui Zhang
- Department of Stomatology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
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40
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Diaz-Vegas A, Sanchez-Aguilera P, Krycer JR, Morales PE, Monsalves-Alvarez M, Cifuentes M, Rothermel BA, Lavandero S. Is Mitochondrial Dysfunction a Common Root of Noncommunicable Chronic Diseases? Endocr Rev 2020; 41:5807952. [PMID: 32179913 PMCID: PMC7255501 DOI: 10.1210/endrev/bnaa005] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Accepted: 03/12/2020] [Indexed: 12/19/2022]
Abstract
Mitochondrial damage is implicated as a major contributing factor for a number of noncommunicable chronic diseases such as cardiovascular diseases, cancer, obesity, and insulin resistance/type 2 diabetes. Here, we discuss the role of mitochondria in maintaining cellular and whole-organism homeostasis, the mechanisms that promote mitochondrial dysfunction, and the role of this phenomenon in noncommunicable chronic diseases. We also review the state of the art regarding the preclinical evidence associated with the regulation of mitochondrial function and the development of current mitochondria-targeted therapeutics to treat noncommunicable chronic diseases. Finally, we give an integrated vision of how mitochondrial damage is implicated in these metabolic diseases.
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Affiliation(s)
- Alexis Diaz-Vegas
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Charles Perkins Centre, School of Life and Environmental Sciences, The University of Sydney, Camperdown, Sydney, NSW, Australia
| | - Pablo Sanchez-Aguilera
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - James R Krycer
- Charles Perkins Centre, School of Life and Environmental Sciences, The University of Sydney, Camperdown, Sydney, NSW, Australia
| | - Pablo E Morales
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Matías Monsalves-Alvarez
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Santiago, Chile
| | - Mariana Cifuentes
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Santiago, Chile.,Center for Studies of Exercise, Metabolism and Cancer (CEMC), Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Beverly A Rothermel
- Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, Texas
| | - Sergio Lavandero
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, Texas.,Center for Studies of Exercise, Metabolism and Cancer (CEMC), Facultad de Medicina, Universidad de Chile, Santiago, Chile
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Molecular modeling and LC-MS-based metabolomics of a glutamine-valproic acid (Gln-VPA) derivative on HeLa cells. Mol Divers 2020; 25:1077-1089. [PMID: 32328963 DOI: 10.1007/s11030-020-10089-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 04/11/2020] [Indexed: 10/24/2022]
Abstract
Glutaminase plays an important role in carcinogenesis and cancer cell growth. This biological target is interesting against cancer cells. Therefore, in this work, in silico [docking and molecular dynamics (MD) simulations] and in vitro methods (antiproliferative and LC-MS metabolomics) were employed to assay a hybrid compound derived from glutamine and valproic acid (Gln-VPA), which was compared with 6-diazo-5-oxo-L-norleucine (DON, a glutaminase inhibitor) and VPA (contained in Gln-VPA structure). Docking results from some snapshots retrieved from MD simulations show that glutaminase recognized Gln-VPA and DON. Additionally, Gln-VPA showed antiproliferative effects in HeLa cells and inhibited glutaminase activity. Finally, the LC-MS-based metabolomics studies on HeLa cells treated with either Gln-VPA (IC60 = 8 mM) or DON (IC50 = 3.5 mM) show different metabolomics behaviors, suggesting that they modulate different biological targets of the cell death mechanism. In conclusion, Gln-VPA is capable of interfering with more than one pharmacological target of cancer, making it an interesting drug that can be used to avoid multitherapy of classic anticancer drugs.
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Abudula A, Rouzi N, Xu L, Yang Y, Hasimu A. Tissue-based metabolomics reveals potential biomarkers for cervical carcinoma and HPV infection. Bosn J Basic Med Sci 2020; 20:78-87. [PMID: 31465717 PMCID: PMC7029203 DOI: 10.17305/bjbms.2019.4359] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 08/27/2019] [Indexed: 12/18/2022] Open
Abstract
Aberrant metabolic regulation has been observed in human cancers, but the corresponding regulation in human papillomavirus (HPV) infection-associated cervical cancer is not well understood. Here, we explored potential biomarkers for the early prediction of cervical carcinoma based on the metabolic profile of uterine cervical tissue specimens that were positive for HPV16 infection. Fifty-two fresh cervical tissues were collected from women confirmed to have cervical squamous cell carcinoma (SCC; n = 21) or cervical intraepithelial neoplasia (CIN) stages II-III (n = 20). Eleven healthy women constituted the controls (negative controls [NCs]). Real-time polymerase chain reaction (PCR) was performed to detect HPV infection in the tissues. High-resolution magic angle spinning nuclear magnetic resonance was utilized for the analysis of the metabolic profile in the tissues. The expression of rate-limiting enzymes involved in key metabolic pathways was detected by reverse-transcription quantitative PCR. An independent immunohistochemical analysis was performed using 123 cases of paraffin-embedded cervical specimens. A profile of 17 small molecular metabolites that showed differential expression in HPV16-positive cervical SCC or CIN II-III compared with HPV-negative NC group was identified. According to the profile, the levels of α- and β-glucose decreased, those of lactate and low-density lipoproteins increased, and the expression of multiple amino acids was altered. Significantly increased transcript and protein levels of glycogen synthase kinase 3 beta (GSK3β) and glutamate decarboxylase 1 (GAD1) and decreased transcript and protein levels of pyruvate kinase muscle isozyme 2 (PKM2) and carnitine palmitoyltransferase 1A (CPT1A) were observed in the patient group (p < 0.05). HPV infection and cervical carcinogenesis drive metabolic modifications that might be associated with the aberrant regulation of enzymes related to metabolic pathways.
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Affiliation(s)
- Abulizi Abudula
- Department of Labour and Environmental Hygienics, School of Public Health, Xinjiang Medical University, Urumqi, China.
| | - Nuermanguli Rouzi
- Department of Labour and Environmental Hygienics, School of Public Health, Xinjiang Medical University, Urumqi, China.
| | - Lixiu Xu
- Department of Pathology, School of Basic Medicine, Xinjiang Medical University, Urumqi, China.
| | - Yun Yang
- Department of Pathology, School of Basic Medicine, Xinjiang Medical University, Urumqi, China.
| | - Axiangu Hasimu
- Department of Pathology, School of Basic Medicine, Xinjiang Medical University, Urumqi, China.
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Yi W, Tu MJ, Liu Z, Zhang C, Batra N, Yu AX, Yu AM. Bioengineered miR-328-3p modulates GLUT1-mediated glucose uptake and metabolism to exert synergistic antiproliferative effects with chemotherapeutics. Acta Pharm Sin B 2020; 10:159-170. [PMID: 31993313 PMCID: PMC6976971 DOI: 10.1016/j.apsb.2019.11.001] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 08/16/2019] [Accepted: 10/31/2019] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs or miRs) are small noncoding RNAs derived from genome to control target gene expression. Recently we have developed a novel platform permitting high-yield production of bioengineered miRNA agents (BERA). This study is to produce and utilize novel fully-humanized BERA/miR-328-3p molecule (hBERA/miR-328) to delineate the role of miR-328-3p in controlling nutrient uptake essential for cell metabolism. We first demonstrated successful high-level expression of hBERA/miR-328 in bacteria and purification to high degree of homogeneity (>98%). Biologic miR-328-3p prodrug was selectively processed to miR-328-3p to suppress the growth of highly-proliferative human osteosarcoma (OS) cells. Besides glucose transporter protein type 1, gene symbol solute carrier family 2 member 1 (GLUT1/SLC2A1), we identified and verified large neutral amino acid transporter 1, gene symbol solute carrier family 7 member 5 (LAT1/SLC7A5) as a direct target for miR-328-3p. While reduction of LAT1 protein levels by miR-328-3p did not alter homeostasis of amino acids within OS cells, suppression of GLUT1 led to a significantly lower glucose uptake and decline in intracellular levels of glucose and glycolytic metabolite lactate. Moreover, combination treatment with hBERA/miR-328 and cisplatin or doxorubicin exerted a strong synergism in the inhibition of OS cell proliferation. These findings support the utility of novel bioengineered RNA molecules and establish an important role of miR-328-3p in the control of nutrient transport and homeostasis behind cancer metabolism.
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Key Words
- 2-NBDG, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxyglucose
- ABCG2, ATP-binding cassette subfamily G member 2
- ACN, acetonitrile
- Au/Uv, absorbance unit of ultraviolet-visible spectroscopy
- BCRP, breast cancer resistant protein
- BERA, bioengineered miRNA agent
- Bioengineered RNA
- CI, combination index
- CPT, cisplatin
- Cancer
- Chemosensitivity
- DOX, doxorubicin
- E. coli, Escherichia coli
- ESI, electrospray ionization
- FPLC, fast protein liquid chromatography
- Fa, fraction affected
- GLUT1
- GLUT1, glucose transporter protein type 1
- HCC, hepatocellular carcinoma
- HPLC, high-performance liquid chromatography
- IS, internal standard
- KRB, Krebs–Ringer bicarbonate
- LAT1
- LAT1, large neutral amino acid transporter 1
- LC–MS/MS, liquid chromatography–tandem mass spectroscopy
- MCT4, monocarboxylate transporter 4
- MRE, miRNA response elements
- MRM, multiple reaction monitoring
- MiR-328
- OS, osteosarcoma
- PAGE, polyacrylamide gel electrophoresis
- PTEN, phosphatase and tensin homolog
- PVDF, Polyvinylidene fluoride
- RAGE, receptor for advanced glycosylation end products
- RT-qPCR, reverse transcription quantitative real-time polymerase chain reaction
- SLC2A1, 7A5, 16A3, solute carrier family 2 member 1, family 7 member 5, family 16 member 3
- WT, wild type
- hBERA, humanized bioengineered miRNA agent
- hsa, Homo sapiens
- htRNASer, human seryl-tRNA
- mTOR, mammalian target of rapamycin
- miR or miRNA, microRNA
- ncRNA, noncoding RNAs
- nt, nucleotide
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Affiliation(s)
- Wanrong Yi
- Department of Orthopaedic Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan 430072, China
- Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento 95817, CA, USA
| | - Mei-Juan Tu
- Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento 95817, CA, USA
| | - Zhenzhen Liu
- Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento 95817, CA, USA
| | - Chao Zhang
- Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento 95817, CA, USA
| | - Neelu Batra
- Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento 95817, CA, USA
| | - Ai-Xi Yu
- Department of Orthopaedic Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan 430072, China
| | - Ai-Ming Yu
- Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento 95817, CA, USA
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Wang FS, Wu WH, Hsiu WS, Liu YJ, Chuang KW. Genome-Scale Metabolic Modeling with Protein Expressions of Normal and Cancerous Colorectal Tissues for Oncogene Inference. Metabolites 2019; 10:metabo10010016. [PMID: 31881674 PMCID: PMC7022839 DOI: 10.3390/metabo10010016] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/10/2019] [Accepted: 12/21/2019] [Indexed: 12/23/2022] Open
Abstract
Although cancer has historically been regarded as a cell proliferation disorder, it has recently been considered a metabolic disease. The first discovery of metabolic alterations in cancer cells refers to Otto Warburg’s observations. Cancer metabolism results in alterations in metabolic fluxes that are evident in cancer cells compared with most normal tissue cells. This study applied protein expressions of normal and cancer cells to reconstruct two tissue-specific genome-scale metabolic models. Both models were employed in a tri-level optimization framework to infer oncogenes. Moreover, this study also introduced enzyme pseudo-coding numbers in the gene association expression to avoid performing posterior decision-making that is necessary for the reaction-based method. Colorectal cancer (CRC) was the topic of this case study, and 20 top-ranked oncogenes were determined. Notably, these dysregulated genes were involved in various metabolic subsystems and compartments. We found that the average similarity ratio for each dysregulation is higher than 98%, and the extent of similarity for flux changes is higher than 93%. On the basis of surveys of PubMed and GeneCards, these oncogenes were also investigated in various carcinomas and diseases. Most dysregulated genes connect to catalase that acts as a hub and connects protein signaling pathways, such as those involving TP53, mTOR, AKT1, MAPK1, EGFR, MYC, CDK8, and RAS family.
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Schmit K, Chen JW, Ayama-Canden S, Fransolet M, Finet L, Demazy C, D'Hondt L, Graux C, Michiels C. Characterization of the role of TMEM45A in cancer cell sensitivity to cisplatin. Cell Death Dis 2019; 10:919. [PMID: 31801939 PMCID: PMC6892797 DOI: 10.1038/s41419-019-2088-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 10/17/2019] [Accepted: 10/18/2019] [Indexed: 12/13/2022]
Abstract
TMEM45A is a transmembrane protein involved in tumor progression and cancer resistance to chemotherapeutic agents in hypoxic condition. It is correlated to a low breast cancer patient overall survival. However, little is known about this protein, in particular the mechanisms by which TMEM45A modulates cancer cell chemosensitivity. In this work, the messenger RNA expression of TMEM45A was assessed in head and neck squamous cell carcinoma (HNSCC) and renal cell carcinoma (RCC) biopsies. TMEM45A was upregulated in patients diagnosed for head and neck or renal cancer. Then, the implication of this protein in cisplatin sensitivity was explored in SQD9 and RCC4 + pVHL cells. TMEM45A inactivation decreased cell proliferation and modulated cell responses to cisplatin. Indeed, TMEM45A inactivation increased the sensitivity of SQD9 cells to cisplatin, whereas it rendered RCC4 + pVHL cells resistant to this anticancer agent. Through RNA-sequencing analysis, we identified several deregulated pathways that indicated that the impact on cisplatin sensitivity may be associated to the inhibition of DNA damage repair and to UPR pathway activation. This study demonstrated, for the first time, an anti or a pro-apoptotic role of this protein depending on the cancer type and highlighted the role of TMEM45A in modulating patient responses to treatment.
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Affiliation(s)
| | - Jia-Wei Chen
- URBC-NARILIS, University of Namur, Namur, Belgium
| | | | | | - Laure Finet
- Université Catholique de Louvain, CHU UCL Namur, Biobank, Yvoir, Belgium
| | | | - Lionel D'Hondt
- Université Catholique de Louvain, CHU UCL Namur, Biobank, Yvoir, Belgium
| | - Carlos Graux
- Université Catholique de Louvain, CHU UCL Namur, Biobank, Yvoir, Belgium
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Kumar P, Agarwal A, Singh AK, Gautam AK, Chakraborti S, Kumar U, Kumar D, Bhattacharya B, Panda P, Saha B, Qidwai T, Maity B, Saha S. Antineoplastic properties of zafirlukast against hepatocellular carcinoma via activation of mitochondrial mediated apoptosis. Regul Toxicol Pharmacol 2019; 109:104489. [DOI: 10.1016/j.yrtph.2019.104489] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 10/01/2019] [Accepted: 10/03/2019] [Indexed: 12/12/2022]
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47
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Hamraz M, Abolhassani R, Andriamihaja M, Ransy C, Lenoir V, Schwartz L, Bouillaud F. Hypertonic external medium represses cellular respiration and promotes Warburg/Crabtree effect. FASEB J 2019; 34:222-236. [PMID: 31914644 DOI: 10.1096/fj.201900706rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 10/04/2019] [Accepted: 10/15/2019] [Indexed: 01/03/2023]
Abstract
Hyperosmotic conditions are associated to several pathological states. In this article, we evaluate the consequence of hyperosmotic medium on cellular energy metabolism. We demonstrate that exposure of cells to hyperosmotic conditions immediately reduces the mitochondrial oxidative phosphorylation rate. This causes an increase in glycolysis, which represses further respiration. This is known as the Warburg or Crabtree effect. In addition to aerobic glycolysis, we observed two other cellular responses that would help to preserve cellular ATP level and viability: A reduction in the cellular ATP turnover rate and a partial mitochondrial uncoupling which is expected to enhance ATP production by Krebs cycle. The latter is likely to constitute another metabolic adaptation to compensate for deficient oxidative phosphorylation that, importantly, is not dependent on glucose.
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Affiliation(s)
- Minoo Hamraz
- Institut Cochin, INSERM, CNRS, Université de Paris, Paris, France
| | | | - Mireille Andriamihaja
- INRA/AgroParisTech UMR 914, Physiologie de la Nutrition et du Comportement Alimentaire, Paris, France
| | - Céline Ransy
- Institut Cochin, INSERM, CNRS, Université de Paris, Paris, France
| | - Véronique Lenoir
- Institut Cochin, INSERM, CNRS, Université de Paris, Paris, France
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48
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Riera Leal A, Ortiz-Lazareno PC, Jave-Suárez LF, Ramírez De Arellano A, Aguilar-Lemarroy A, Ortiz-García YM, Barrón-Gallardo CA, Solís-Martínez R, Luquin De Anda S, Muñoz-Valle JF, Pereira-Suárez AL. 17β‑estradiol‑induced mitochondrial dysfunction and Warburg effect in cervical cancer cells allow cell survival under metabolic stress. Int J Oncol 2019; 56:33-46. [PMID: 31746421 PMCID: PMC6910176 DOI: 10.3892/ijo.2019.4912] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 08/19/2019] [Indexed: 02/07/2023] Open
Abstract
Mitochondria from different types of cancer show bioenergetics and dysfunction that favor cell proliferation. The mechanistic understanding of estrogen in cervical cancer is poorly understood. Therefore, the objective of this study was to determine how 17β-estradiol (E2) affects mitochondrial function and the Warburg effect in SiHa, HeLa and C33A cervical cancer cells. Mitochondrial compromise was evaluated measuring changes in the membrane permeability by immunofluorescence, calcium concentration, redox status, iron and ferritin reserves. Glucose consumption and lactic acid assays were used to detect the metabolic activity. Results were confirmed at molecular level by analysis of the differential gene expression using RNA sequencing. E2 modified the mitochondrial permeability and produced an alteration in the calcium signaling pathway. In HeLa and SiHa, there was a significant decrease in nitric oxide levels and lipid peroxidation, and an increase in glucose consumption and lactic acid levels when stimulated with E2. Intracellular iron or ferritin reserves were not affected by the E2 treatment. Genes differentially modulated by E2 were involved in the mitochondrial electron transport chain, oxidative phosphorylation system, glycolysis, pentose phosphate pathway and the regulation of metabolic signaling pathways. Herein, we provide evidence for a primary effect of estrogen on mitochondrial function and the Warburg effect, favoring the metabolic adaptation of the cervical cancer cell lines and their survival.
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Affiliation(s)
- Annie Riera Leal
- Laboratory of Immunology, Department of Physiology, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Pablo César Ortiz-Lazareno
- Division of Immunology, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
| | - Luis Felipe Jave-Suárez
- Division of Immunology, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
| | - Adrián Ramírez De Arellano
- Research Institute in Biomedical Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Adriana Aguilar-Lemarroy
- Division of Immunology, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
| | - Yveth Marlene Ortiz-García
- Laboratory of Immunology, Department of Physiology, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Carlos Alfredo Barrón-Gallardo
- Division of Immunology, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
| | - Raúl Solís-Martínez
- Diagnostic Laboratory, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Sonia Luquin De Anda
- Department of Neurosciences, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - José Francisco Muñoz-Valle
- Research Institute in Biomedical Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Ana Laura Pereira-Suárez
- Division of Immunology, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
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Lue KH, Wu YF, Liu SH, Hsieh TC, Chuang KS, Lin HH, Chen YH. Prognostic Value of Pretreatment Radiomic Features of 18F-FDG PET in Patients With Hodgkin Lymphoma. Clin Nucl Med 2019; 44:e559-e565. [PMID: 31306204 DOI: 10.1097/rlu.0000000000002732] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE This study investigated whether a radiomic analysis of pretreatment F-FDG PET can predict prognosis in patients with Hodgkin lymphoma (HL). METHODS Forty-two patients who were diagnosed as having HL and underwent pretreatment F-FDG PET scans were retrospectively enrolled. For each patient, we extracted 450 radiomic features from PET images. The prognostic significance of the clinical and radiomic features was assessed in relation to progression-free survival (PFS) and overall survival (OS). Receiver operating characteristic curve, Cox proportional hazards regression, and Kaplan-Meier analyses were performed to examine the potential independent predictors and to evaluate the predictive value. RESULTS Intensity nonuniformity extracted from a gray-level run-length matrix and the Ann Arbor stage were independently associated with PFS (hazard ratio [HR] = 22.8, P < 0.001; HR = 7.6, P = 0.024) and OS (HR = 14.5, P = 0.012; HR = 8.5, P = 0.048), respectively. In addition, SUV kurtosis was an independent prognosticator for PFS (HR = 6.6, P = 0.026). We devised a prognostic scoring system based on these 3 risk predictors. The proposed scoring system further improved the risk stratification of the current staging classification (P < 0.001). CONCLUSIONS The radiomic feature intensity nonuniformity is an independent prognostic predictor of PFS and OS in patients with HL. We devised a prognostic scoring system, which may be more beneficial for patient risk stratification in guiding therapy compared with the current Ann Arbor staging system.
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Affiliation(s)
- Kun-Han Lue
- From the Department of Nuclear Medicine, Buddhist Tzu Chi General Hospital, Hualien.,Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu
| | - Yi-Feng Wu
- Department of Hematology and Oncology, Buddhist Tzu Chi General Hospital
| | - Shu-Hsin Liu
- From the Department of Nuclear Medicine, Buddhist Tzu Chi General Hospital, Hualien.,Department of Medical Imaging and Radiological Sciences, Tzu Chi University of Science and Technology
| | | | - Keh-Shih Chuang
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu
| | - Hsin-Hon Lin
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu.,Department of Radiation Oncology, Chang Gung Memorial Hospital.,Medical Physics Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yu-Hung Chen
- From the Department of Nuclear Medicine, Buddhist Tzu Chi General Hospital, Hualien
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50
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Jeong KY. Cancer-specific metabolism: Promising approaches for colorectal cancer treatment. World J Gastrointest Oncol 2019. [PMID: 31662818 DOI: 10.4251/wjgo.v11.i10.768.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Investigation of cancer-specific metabolism has made it possible to establish the principle that atypically reconstituted metabolism is considered a hallmark of cancer due to changes in physiological property. Recently, a variety of targets depending on the prompted aerobic glycolysis process, starting from the abnormal uptake of glucose, and cancer-specific metabolism due to impaired mitochondrial function and abnormal expression of drug-metabolizing enzymes have been investigated and discovered. Given that most solid cancers rely on cancer-specific metabolism to support their growth, it is necessary to examine closely the specific processes of cancer metabolism and have a detailed understanding of how cellular metabolism is altered in colorectal cancer (CRC) related to CRC survival and proliferation. The development of key methods to regulate efficiently cancer-specific metabolism in CRC is still in the initial stage. Therefore, targeting cancer-specific metabolism will yield treatable methods that are critical as a new area of development strategies for CRC treatment.
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Affiliation(s)
- Keun-Yeong Jeong
- The Research Center, Metimedi Pharmaceuticals, Incheon 22006, South Korea.
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