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Bu J, Miao Z, Yang Q. GOT2: New therapeutic target in pancreatic cancer. Genes Dis 2025; 12:101370. [PMID: 40247913 PMCID: PMC12005923 DOI: 10.1016/j.gendis.2024.101370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 04/18/2024] [Accepted: 06/21/2024] [Indexed: 04/19/2025] Open
Abstract
In recent years, the incidence and mortality rates of pancreatic cancer have been steadily increasing, and conventional therapies have shown a high degree of tolerance. Therefore, the search for new therapeutic targets remains a key issue in current research. Mitochondrial glutamic-oxaloacetic transaminase 2 (GOT2) is an important component of the malate-aspartate shuttle system, which plays an important role in the maintenance of cellular redox balance and amino acid metabolism, and has the potential to become a promising target for anti-cancer therapy. In this paper, we will elaborate on the metabolic and immune effects of GOT2 in pancreatic cancer based on existing studies, with a view to opening up new avenues for the treatment of pancreatic cancer.
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Affiliation(s)
- Jiarui Bu
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Zeyu Miao
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Qing Yang
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
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2
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Shi J, Cui X, Wang J, Liu G, Meng J, Zhang Y. Crosstalk between the tumor immune microenvironment and metabolic reprogramming in pancreatic cancer: new frontiers in immunotherapy. Front Immunol 2025; 16:1564603. [PMID: 40356913 PMCID: PMC12066759 DOI: 10.3389/fimmu.2025.1564603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 04/07/2025] [Indexed: 05/15/2025] Open
Abstract
In recent years, the incidence and mortality of pancreatic cancer (PC) are increasing year by year. The highly heterogeneous nature of PC, its strong immune escape ability and easy metastasis make it the most lethal malignant tumor in the world. With the rapid development of sequencing technology, the complex components in the tumor microenvironment (TME) of PC have been gradually revealed. Interactions between pancreatic stellate cells, tumor-associated fibroblasts, various types of immune cells, and cancer cells collectively promote metabolic reprogramming of all types of cells. This metabolic reprogramming further enhances the immune escape mechanism of tumor cells and ultimately induces tumor cells to become severely resistant to chemotherapy and immunotherapy. On the one hand, PC cells achieve re and rational utilization of glucose, amino acids and lipids through metabolic reprogramming, which in turn accomplishes biosynthesis and energy metabolism requirements. Under such conditions, tumorigenesis, proliferation and metastasis are ultimately promoted. On the other hand, various types of immune cells in the tumor immune microenvironment (TIME) also undergo metabolic reprogramming, which leads to tumor progression and suppression of anti-immune responses by inhibiting the function of normal anti-tumor immune cells and enhancing the function of immunosuppressive cells. The aim of this review is to explore the interaction between the immune microenvironment and metabolic reprogramming in PC. The focus is to summarize the specific mechanisms of action of metabolic reprogramming of PC cells and metabolic reprogramming of immune cells. In addition, this review will summarize the mechanisms of immunotherapy resistance in PC cells. In the future, targeting specific mechanisms of metabolic reprogramming will provide a solid theoretical basis for the development of combination therapies for PC.
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Affiliation(s)
- Jintai Shi
- College of Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiaoyan Cui
- Pharmacy Department, Jinan Huaiyin People’s Hospital, Jinan, China
| | - Junlin Wang
- Department of Pharmacy, Shandong University Second People’s Hospital, Jinan, China
| | - Guangqia Liu
- Department of Pharmacy, Jinan Licheng District Liubu Town Health Centre, Jinan, China
| | - Jiayin Meng
- Department of Pharmacy, Jinan Second People’s Hospital, Jinan, China
| | - Yingjie Zhang
- College of Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
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3
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Meng Y, Zhou Q, Dian Y, Zeng F, Deng G, Chen X. Ferroptosis: A Targetable Vulnerability for Melanoma Treatment. J Invest Dermatol 2025:S0022-202X(24)03024-0. [PMID: 39797894 DOI: 10.1016/j.jid.2024.11.007] [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: 08/08/2024] [Revised: 11/10/2024] [Accepted: 11/11/2024] [Indexed: 01/13/2025]
Abstract
Melanoma is a devastating form of skin cancer characterized by a high mutational burden, limited treatment success, and dismal prognosis. Although immunotherapy and targeted therapies have significantly revolutionized melanoma treatment, the majority of patients fail to achieve durable responses, highlighting the urgent need for novel therapeutic strategies. Ferroptosis, an iron-dependent form of regulated cell death driven by the overwhelming accumulation of lipid peroxides, has emerged as a promising therapeutic approach in preclinical melanoma models. A deeper understanding of the ferroptosis landscape in melanoma based on its biology characteristics, including phenotypic plasticity, metabolic state, genomic alterations, and epigenetic changes, as well as the complex role and mechanisms of ferroptosis in immune cells could provide a foundation for developing effective treatments. In this review, we outline the molecular mechanisms of ferroptosis, decipher the role of melanoma biology in ferroptosis regulation, reveal the therapeutic potential of ferroptosis in melanoma, and discuss the pressing questions that should guide future investigations into ferroptosis in melanoma.
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Affiliation(s)
- Yu Meng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China; Furong Laboratory, Changsha, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Qian Zhou
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China; Furong Laboratory, Changsha, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Yating Dian
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China; Furong Laboratory, Changsha, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Furong Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Guangtong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China; Furong Laboratory, Changsha, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China.
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China; Furong Laboratory, Changsha, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China.
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4
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Maiti A, Mondal S, Choudhury S, Bandopadhyay A, Mukherjee S, Sikdar N. Oncometabolites in pancreatic cancer: Strategies and its implications. World J Exp Med 2024; 14:96005. [PMID: 39713078 PMCID: PMC11551704 DOI: 10.5493/wjem.v14.i4.96005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 08/24/2024] [Accepted: 09/14/2024] [Indexed: 10/31/2024] Open
Abstract
Pancreatic cancer (PanCa) is a catastrophic disease, being third lethal in both the genders around the globe. The possible reasons are extreme disease invasiveness, highly fibrotic and desmoplastic stroma, dearth of confirmatory diagnostic approaches and resistance to chemotherapeutics. This inimitable tumor microenvironment (TME) or desmoplasia with excessive extracellular matrix accumulation, create an extremely hypovascular, hypoxic and nutrient-deficient zone inside the tumor. To survive, grow and proliferate in such tough TME, pancreatic tumor and stromal cells transform their metabolism. Transformed glucose, glutamine, fat, nucleotide metabolism and inter-metabolite communication between tumor and TME in synergism, impart therapy resistance, and immunosuppression in PanCa. Thus, a finer knowledge of altered metabolism would uncover its metabolic susceptibilities. These unique metabolic targets may help to device novel diagnostic/prognostic markers and therapeutic strategies for better management of PanCa. In this review, we sum up reshaped metabolic pathways in PanCa to formulate detection and remedial strategies of this devastating disease.
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Affiliation(s)
- Arunima Maiti
- Suraksha Diagnostics Pvt Ltd, Newtown, Rajarhat, Kolkata 700156, West Bengal, India
| | - Susmita Mondal
- Department of Zoology, Diamond Harbour Women’s University, Diamond Harbour 743368, West Bengal, India
| | - Sounetra Choudhury
- Human Genetics Unit, Indian Statistical Institute, Kolkata 700108, West Bengal, India
| | | | - Sanghamitra Mukherjee
- Department of Pathology, RG Kar Medical College and Hospital, Kolkata 700004, West Bengal, India
| | - Nilabja Sikdar
- Human Genetics Unit, Indian Statistical Institute, Kolkata 700108, West Bengal, India
- Scientist G, Estuarine and Coastal Studies Foundation, Howrah 711101, West Bengal, India
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5
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Zhang S, He R, Zhang M, Zhang J, Wu M, Zhang G, Jiang T. Elucidation of the Role of SHMT2 in L-Serine Homeostasis in Hypoxic Hepa1-6 Cells. Int J Mol Sci 2024; 25:11786. [PMID: 39519335 PMCID: PMC11545941 DOI: 10.3390/ijms252111786] [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: 09/28/2024] [Revised: 10/21/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
Hypoxia is a characteristic feature of malignancy; however, its effect on metabolism remains unclear. In this study, Hepa1-6 cells were cultured under hypoxic conditions and their metabolites were analyzed. Elevated levels of L-serine along with increased glycolytic activity are prominent features of hypoxia. Transcriptome sequencing revealed the downregulation of genes involved in L-serine synthesis and metabolism, which was confirmed by PCR analysis and comparison with public databases. Further experimental evidence indicates that the accumulation of L-serine under hypoxic conditions is attributable not only to enhanced glycolysis but also to a reduction in the catabolism of L-serine mediated by serine hydroxymethyltransferase 2 (SHMT2).
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Affiliation(s)
- Shuo Zhang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; (S.Z.); (R.H.); (J.Z.); (M.W.)
| | - Ruoxu He
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; (S.Z.); (R.H.); (J.Z.); (M.W.)
| | - Mingsi Zhang
- Musculoskeletal Sport Science and Health, Loughborough University, Loughborough LE11 3TU, UK;
| | - Jingcheng Zhang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; (S.Z.); (R.H.); (J.Z.); (M.W.)
| | - Mengting Wu
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; (S.Z.); (R.H.); (J.Z.); (M.W.)
| | - Guangji Zhang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; (S.Z.); (R.H.); (J.Z.); (M.W.)
- Zhejiang Key Laboratory of Blood-Stasis-Toxin Syndrome, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Tao Jiang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; (S.Z.); (R.H.); (J.Z.); (M.W.)
- Zhejiang Key Laboratory of Blood-Stasis-Toxin Syndrome, Zhejiang Chinese Medical University, Hangzhou 310053, China
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6
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Yin H, Liu Y, Dong Q, Wang H, Yan Y, Wang X, Wan X, Yuan G, Pan Y. The mechanism of extracellular CypB promotes glioblastoma adaptation to glutamine deprivation microenvironment. Cancer Lett 2024; 597:216862. [PMID: 38582396 DOI: 10.1016/j.canlet.2024.216862] [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: 02/13/2024] [Revised: 03/21/2024] [Accepted: 04/01/2024] [Indexed: 04/08/2024]
Abstract
Glioblastoma, previously known as glioblastoma multiform (GBM), is a type of glioma with a high degree of malignancy and rapid growth rate. It is highly dependent on glutamine (Gln) metabolism during proliferation and lags in neoangiogenesis, leading to extensive Gln depletion in the core region of GBM. Gln-derived glutamate is used to synthesize the antioxidant Glutathione (GSH). We demonstrated that GSH levels are also reduced in Gln deficiency, leading to increased reactive oxygen species (ROS) levels. The ROS production induces endoplasmic reticulum (ER) stress, and the proteins in the ER are secreted into the extracellular medium. We collected GBM cell supernatants cultured with or without Gln medium; the core and peripheral regions of human GBM tumor tissues. Proteomic analysis was used to screen out the target-secreted protein CypB. We demonstrated that the extracellular CypB expression is associated with Gln deprivation. Then, we verified that GBM can promote the glycolytic pathway by activating HIF-1α to upregulate the expression of GLUT1 and LDHA. Meanwhile, the DRP1 was activated, increasing mitochondrial fission, thus inhibiting mitochondrial function. To explore the specific mechanism of its regulation, we constructed a si-CD147 knockout model and added human recombinant CypB protein to verify that extracellular CypB influenced the expression of downstream p-AKT through its cell membrane receptor CD147 binding. Moreover, we confirmed that p-AKT could upregulate HIF-1α and DRP1. Finally, we observed that extracellular CypB can bind to the CD147 receptor, activate p-AKT, upregulate HIF-1α and DRP1 in order to promote glycolysis while inhibiting mitochondrial function to adapt to the Gln-deprived microenvironment.
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Affiliation(s)
- Hang Yin
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Yang Liu
- Laboratory of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China; Neurological Diseases Clinical Medical Research Center of Gansu Province, Lanzhou, China
| | - Qiang Dong
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Hongyu Wang
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Yunji Yan
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Xiaoqing Wang
- Laboratory of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China; Neurological Diseases Clinical Medical Research Center of Gansu Province, Lanzhou, China
| | - Xiaoyu Wan
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Crescen, Singapore, Singapore; School of Basic Medicine, Henan University, Kaifeng, China
| | - Guoqiang Yuan
- Laboratory of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China; Neurological Diseases Clinical Medical Research Center of Gansu Province, Lanzhou, China.
| | - Yawen Pan
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China.
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7
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Venkateswaran N, Garcia R, Lafita-Navarro MC, Hao YH, Perez-Castro L, Nogueira PAS, Solmonson A, Mender I, Kilgore JA, Fang S, Brown IN, Li L, Parks E, Lopes Dos Santos I, Bhaskar M, Kim J, Jia Y, Lemoff A, Grishin NV, Kinch L, Xu L, Williams NS, Shay JW, DeBerardinis RJ, Zhu H, Conacci-Sorrell M. Tryptophan fuels MYC-dependent liver tumorigenesis through indole 3-pyruvate synthesis. Nat Commun 2024; 15:4266. [PMID: 38769298 PMCID: PMC11106337 DOI: 10.1038/s41467-024-47868-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 04/09/2024] [Indexed: 05/22/2024] Open
Abstract
Cancer cells exhibit distinct metabolic activities and nutritional dependencies compared to normal cells. Thus, characterization of nutrient demands by individual tumor types may identify specific vulnerabilities that can be manipulated to target the destruction of cancer cells. We find that MYC-driven liver tumors rely on augmented tryptophan (Trp) uptake, yet Trp utilization to generate metabolites in the kynurenine (Kyn) pathway is reduced. Depriving MYC-driven tumors of Trp through a No-Trp diet not only prevents tumor growth but also restores the transcriptional profile of normal liver cells. Despite Trp starvation, protein synthesis remains unhindered in liver cancer cells. We define a crucial role for the Trp-derived metabolite indole 3-pyruvate (I3P) in liver tumor growth. I3P supplementation effectively restores the growth of liver cancer cells starved of Trp. These findings suggest that I3P is a potential therapeutic target in MYC-driven cancers. Developing methods to target this metabolite represents a potential avenue for liver cancer treatment.
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Affiliation(s)
- Niranjan Venkateswaran
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Roy Garcia
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - M Carmen Lafita-Navarro
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Yi-Heng Hao
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Lizbeth Perez-Castro
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Pedro A S Nogueira
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Ashley Solmonson
- Children's Medical Center Research Institute at University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Ilgen Mender
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Jessica A Kilgore
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Shun Fang
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Isabella N Brown
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Li Li
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Emily Parks
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Igor Lopes Dos Santos
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Mahima Bhaskar
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Jiwoong Kim
- Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Yuemeng Jia
- Children's Medical Center Research Institute at University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Andrew Lemoff
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Nick V Grishin
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Lisa Kinch
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Lin Xu
- Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Noelle S Williams
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Jerry W Shay
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Ralph J DeBerardinis
- Children's Medical Center Research Institute at University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Hao Zhu
- Children's Medical Center Research Institute at University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Maralice Conacci-Sorrell
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
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8
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Pathiriparambath MSR, Joseph M, Manog M, Thomas V, Tharayil H, Nair LV. Glutamic Acid Modified Gold Nanorod Sensor for the Detection of Calcium ions in Neuronal Cells. Chembiochem 2024; 25:e202400009. [PMID: 38545627 DOI: 10.1002/cbic.202400009] [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: 01/03/2024] [Revised: 03/10/2024] [Indexed: 04/18/2024]
Abstract
Calcium (Ca2+) ions play a crucial role in the functioning of neurons, governing various aspects of neuronal activity such as rapid modulation and alterations in gene expression. Ca2+ signaling has a significant impact on the development of diseases and the impairment of neuronal functions. Herein, the study reports a Ca2+ ion sensor in neuronal cells using a gold nanorod. The gold nanorod (GA-GNR) conjugated glutamic acid developed in the study was used as a nano-bio probe for the experimental and in vitro detection of calcium. The nanosensor is colloidally stable, preserves plasmonic properties, and shows good viability in neuronal cells, as well as promoting neuron cell line growth. The cytotoxicity and cell penetration of the nanosensor are studied using Raman spectroscopy, brightfield and darkfield microscopy imaging, and MTT assays. The quantification of Ca2+ ions in neuronal cells is determined by monitoring the surface plasmon resonance (SPR) of the GA-GNR. The change in the intensity profile in the presence of Ca2+ incubated neurons was effectively used to develop a portable prototype of an optical Ca2+ sensor, proposing it as a tool for neurodegenerative disease diagnosis and neuromodulation evaluation.
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Affiliation(s)
| | - Merin Joseph
- Department of Materials Science and Engineering, National Institute of Technology Calicut, Kozhikode, 673601, Kerala, India
| | - Mithun Manog
- Department of Materials Science and Engineering, National Institute of Technology Calicut, Kozhikode, 673601, Kerala, India
| | - Vinoy Thomas
- Department of Mechanical and Materials Engineering, University Alabama at Birmingham, USA
| | - Hanas Tharayil
- Department of Materials Science and Engineering, National Institute of Technology Calicut, Kozhikode, 673601, Kerala, India
| | - Lakshmi V Nair
- Department of Materials Science and Engineering, National Institute of Technology Calicut, Kozhikode, 673601, Kerala, India
- Department of Mechanical and Materials Engineering, University Alabama at Birmingham, USA
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9
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Devitt AN, Vargas AL, Zhu W, Des Soye BJ, Butun FA, Alt T, Kaley N, Ferreira GM, Moran G, Kelleher NL, Liu D, Silverman RB. Design, Synthesis, and Mechanistic Studies of ( R)-3-Amino-5,5-difluorocyclohex-1-ene-1-carboxylic Acid as an Inactivator of Human Ornithine Aminotransferase. ACS Chem Biol 2024; 19:1066-1081. [PMID: 38630468 PMCID: PMC11274680 DOI: 10.1021/acschembio.4c00022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/20/2024]
Abstract
Human ornithine aminotransferase (hOAT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme, has been shown to play an essential role in the metabolic reprogramming and progression of hepatocellular carcinoma (HCC). HCC accounts for approximately 75% of primary liver cancers and is within the top three causes of cancer death worldwide. As a result of treatment limitations, the overall 5-year survival rate for all patients with HCC is under 20%. The prevalence of HCC necessitates continued development of novel and effective treatment methods. In recent years, the therapeutic potential of selective inactivation of hOAT has been demonstrated for the treatment of HCC. Inspired by previous increased selectivity for hOAT by the expansion of the cyclopentene ring scaffold to a cyclohexene, we designed, synthesized, and evaluated a series of novel fluorinated cyclohexene analogues and identified (R)-3-amino-5,5-difluorocyclohex-1-ene-1-carboxylic acid as a time-dependent inhibitor of hOAT. Structural and mechanistic studies have elucidated the mechanism of inactivation of hOAT by 5, resulting in a PLP-inactivator adduct tightly bound to the active site of the enzyme. Intact protein mass spectrometry, 19F NMR spectroscopy, transient state kinetic studies, and X-ray crystallography were used to determine the structure of the final adduct and elucidate the mechanisms of inactivation. Interestingly, despite the highly electrophilic intermediate species conferred by fluorine and structural evidence of solvent accessibility in the hOAT active site, Lys292 and water did not participate in nucleophilic addition during the inactivation mechanism of hOAT by 5. Instead, rapid aromatization to yield the final adduct was favored.
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Affiliation(s)
- Allison N. Devitt
- Department of Chemistry, Chemistry of Life Processes Institute, and Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois 60208, United States
| | - Abigail L. Vargas
- Department of Chemistry and Biochemistry, Loyola University Chicago, Chicago, Illinois 60660, United States
| | - Wei Zhu
- Department of Chemistry, Chemistry of Life Processes Institute, and Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois 60208, United States
| | - Benjamin James Des Soye
- Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208, United States
| | - Fatma Ayaloglu Butun
- Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208, United States
| | - Tyler Alt
- Department of Chemistry and Biochemistry, Loyola University Chicago, Chicago, Illinois 60660, United States
| | - Nicholas Kaley
- Department of Chemistry and Biochemistry, Loyola University Chicago, Chicago, Illinois 60660, United States
| | - Glaucio M. Ferreira
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, SP, Brazil
| | - Graham Moran
- Department of Chemistry and Biochemistry, Loyola University Chicago, Chicago, Illinois 60660, United States
| | - Neil L. Kelleher
- Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208, United States
| | - Dali Liu
- Department of Chemistry and Biochemistry, Loyola University Chicago, Chicago, Illinois 60660, United States
| | - Richard B. Silverman
- Department of Chemistry, Chemistry of Life Processes Institute, and Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois 60208, United States
- Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208, United States
- Department of Pharmacology, Northwestern University, Chicago, Illinois, 60611, United States
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10
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Tang T, Fang D, Ji Z, Zhong Z, Zhou B, Ye L, Jiang L, Sun X. Inhibition of thioredoxin-1 enhances the toxicity of glycolysis inhibitor 2-deoxyglucose by downregulating SLC1A5 expression in colorectal cancer cells. Cell Oncol (Dordr) 2024; 47:607-621. [PMID: 37867183 DOI: 10.1007/s13402-023-00887-6] [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] [Accepted: 09/29/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND Targeting glycolysis in cancer is an attractive approach for therapeutic intervention. 2-Deoxyglucose (2DG) is a synthetic glucose analog that inhibits glycolysis. However, its efficacy is limited by the systemic toxicity at high doses. Understanding the mechanism of 2DG resistance is important for further use of this drug in cancer treatment. METHODS The expression of thioredoxin-1 (Trx-1) in colorectal cancer (CRC) cells treated with 2DG was detected by Western blotting. The effect of Trx-1 on the cytotoxicity of 2DG in CRC cells was examined in vitro and in vivo. The molecular mechanism involved in Trx-1-mediated activation of the SLC1A5 gene promoter activity was elucidated using in vitro models. RESULTS Inhibition glycolysis with 2DG increased the expression of Trx-1 in CRC cells. Overexpression of Trx-1 decreased the cytotoxicity of 2DG, whereas knockdown of Trx-1 by shRNA significantly increased the cytotoxicity of 2DG in CRC cells. The Trx-1 inhibitor PX-12 increased the cytotoxicity of 2DG on CRC cells both in vitro and in vivo. In addition, Trx-1 promoted SLC1A5 expression by increasing the promoter activity of the SLC1A5 gene by binding to SP1. We also found that the SLC1A5 expression was upregulated in CRC tissues, and inhibition of SLC1A5 significantly enhanced the inhibitory effect of 2DG on the growth of CRC cells in vitro and in vivo. Overexpression of SLC1A5 reduced the cytotoxicity of 2DG in combination with PX-12 treatment in CRC cells. CONCLUSION Our results demonstrate a novel adaptive mechanism of glycolytic inhibition in which Trx-1 increases GSH levels by regulating SLC1A5 to rescue cytotoxicity induced by 2DG in CRC cells. Inhibition of glycolysis in combination with inhibition of Trx-1 or SLC1A5 may be a promising strategy for the treatment of CRC.
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Affiliation(s)
- Tianbin Tang
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Daoquan Fang
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Ziwei Ji
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou, 317000, China
| | - Zuyue Zhong
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Baojian Zhou
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Lechi Ye
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Lei Jiang
- Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Xuecheng Sun
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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11
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Zhang Z, Liang X, Yang X, Liu Y, Zhou X, Li C. Advances in Nanodelivery Systems Based on Metabolism Reprogramming Strategies for Enhanced Tumor Therapy. ACS APPLIED MATERIALS & INTERFACES 2024; 16:6689-6708. [PMID: 38302434 DOI: 10.1021/acsami.3c15686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
Tumor development and metastasis are closely related to the complexity of the metabolism network. Recently, metabolism reprogramming strategies have attracted much attention in tumor metabolism therapy. Although there is preliminary success of metabolism therapy agents, their therapeutic effects have been restricted by the effective reaching of the tumor sites of drugs. Nanodelivery systems with unique physical properties and elaborate designs can specifically deliver to the tumors. In this review, we first summarize the research progress of nanodelivery systems based on tumor metabolism reprogramming strategies to enhance therapies by depleting glucose, inhibiting glycolysis, depleting lactic acid, inhibiting lipid metabolism, depleting glutamine and glutathione, and disrupting metal metabolisms combined with other therapies, including chemotherapy, radiotherapy, photodynamic therapy, etc. We further discuss in detail the advantages of nanodelivery systems based on tumor metabolism reprogramming strategies for tumor therapy. As well as the opportunities and challenges for integrating nanodelivery systems into tumor metabolism therapy, we analyze the outlook for these emerging areas. This review is expected to improve our understanding of modulating tumor metabolisms for enhanced therapy.
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Affiliation(s)
- Zongquan Zhang
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Xiaoya Liang
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Xi Yang
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Yan Liu
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Xiangyu Zhou
- Department of Thyroid and Vascular Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
- Basic Medicine Research Innovation Center for Cardiometabolic Disease, Ministry of Education, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Chunhong Li
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
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12
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Jiang X, Peng Q, Peng M, Oyang L, Wang H, Liu Q, Xu X, Wu N, Tan S, Yang W, Han Y, Lin J, Xia L, Tang Y, Luo X, Dai J, Zhou Y, Liao Q. Cellular metabolism: A key player in cancer ferroptosis. Cancer Commun (Lond) 2024; 44:185-204. [PMID: 38217522 PMCID: PMC10876208 DOI: 10.1002/cac2.12519] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 12/25/2023] [Accepted: 01/02/2024] [Indexed: 01/15/2024] Open
Abstract
Cellular metabolism is the fundamental process by which cells maintain growth and self-renewal. It produces energy, furnishes raw materials, and intermediates for biomolecule synthesis, and modulates enzyme activity to sustain normal cellular functions. Cellular metabolism is the foundation of cellular life processes and plays a regulatory role in various biological functions, including programmed cell death. Ferroptosis is a recently discovered form of iron-dependent programmed cell death. The inhibition of ferroptosis plays a crucial role in tumorigenesis and tumor progression. However, the role of cellular metabolism, particularly glucose and amino acid metabolism, in cancer ferroptosis is not well understood. Here, we reviewed glucose, lipid, amino acid, iron and selenium metabolism involvement in cancer cell ferroptosis to elucidate the impact of different metabolic pathways on this process. Additionally, we provided a detailed overview of agents used to induce cancer ferroptosis. We explained that the metabolism of tumor cells plays a crucial role in maintaining intracellular redox homeostasis and that disrupting the normal metabolic processes in these cells renders them more susceptible to iron-induced cell death, resulting in enhanced tumor cell killing. The combination of ferroptosis inducers and cellular metabolism inhibitors may be a novel approach to future cancer therapy and an important strategy to advance the development of treatments.
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Affiliation(s)
- Xianjie Jiang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, P. R. China
| | - Qiu Peng
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, P. R. China
| | - Mingjing Peng
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, P. R. China
| | - Linda Oyang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, P. R. China
| | - Honghan Wang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Department of Head and Neck Surgery, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
| | - Qiang Liu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, P. R. China
| | - Xuemeng Xu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Hengyang Medical School, University of South China, Hengyang, Hunan, P. R. China
| | - Nayiyuan Wu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, P. R. China
| | - Shiming Tan
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
| | - Wenjuan Yang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
| | - Yaqian Han
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, P. R. China
| | - Jinguan Lin
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
| | - Longzheng Xia
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
| | - Yanyan Tang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, P. R. China
| | - Xia Luo
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, P. R. China
| | - Jie Dai
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Department of Head and Neck Surgery, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
| | - Yujuan Zhou
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, P. R. China
| | - Qianjin Liao
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Public Service Platform of Tumor Organoids Technology, Changsha, Hunan, P. R. China
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13
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Ren LL, Mao T, Meng P, Zhang L, Wei HY, Tian ZB. Glutamine addiction and therapeutic strategies in pancreatic cancer. World J Gastrointest Oncol 2023; 15:1852-1863. [DOI: 10.4251/wjgo.v15.i11.1852] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 09/06/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Pancreatic cancer remains one of the most lethal diseases worldwide owing to its late diagnosis, early metastasis, and poor prognosis. Because current therapeutic options are limited, there is an urgent need to investigate novel targeted treatment strategies. Pancreatic cancer faces significant metabolic challenges, principally hypoxia and nutrient deprivation, due to specific microenvironmental constraints, including an extensive desmoplastic stromal reaction. Pancreatic cancer cells have been shown to rewire their metabolism and energy production networks to support rapid survival and proliferation. Increased glucose uptake and glycolytic pathway activity during this process have been extensively described. However, growing evidence suggests that pancreatic cancer cells are glutamine addicted. As a nitrogen source, glutamine directly (or indirectly via glutamate conversion) contributes to many anabolic processes in pancreatic cancer, including amino acids, nucleobases, and hexosamine biosynthesis. It also plays an important role in redox homeostasis, and when converted to α-ketoglutarate, glutamine serves as an energy and anaplerotic carbon source, replenishing the tricarboxylic acid cycle intermediates. The present study aims to provide a comprehensive overview of glutamine metabolic reprogramming in pancreatic cancer, focusing on potential therapeutic approaches targeting glutamine metabolism in pancreatic cancer.
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Affiliation(s)
- Lin-Lin Ren
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Tao Mao
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Pin Meng
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Li Zhang
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Hong-Yun Wei
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Zi-Bin Tian
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
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14
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Cheng L, Zhai H, Du J, Zhang G, Shi G. Lobetyolin inhibits cell proliferation and induces cell apoptosis by downregulating ASCT2 in gastric cancer. Cytotechnology 2023; 75:435-448. [PMID: 37655270 PMCID: PMC10465467 DOI: 10.1007/s10616-023-00588-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 06/29/2023] [Indexed: 09/02/2023] Open
Abstract
Gastric cancer (GC) is a heterogeneous disease and is the fifth most common cancer worldwide. Lobetyolin, as a bioactive ingredient extracted from Codonopsis pilosula (Franch.) Nannf., has been reported to exert anti-tumor effects in several cancer types. This study was aimed to investigate the role of lobetyolin in GC and the associated mechanism. MKN-45 and MKN-28 cells were incubated with concentrations of lobetyolin for 24 h. The viability and survival of GC cells were evaluated by performing MTT assay. Glutamine uptake, Adenosine Triphosphate, reactive oxygen species (ROS), and glutathione levels were measured by corresponding kits. Apoptosis and mitochondrial membrane potential of GC cells were determined by flow cytometry. Alanine, serine, cysteine-preferring transporter 2 (ASCT2) and the AKT/GSK3β/c-Myc pathway protein levels were examined by western blotting. Xenograft model and immunohistochemical staining were used to evaluate the pharmacological effects of lobetyolin in mice in vivo. We found that lobetyolin treatment suppressed the proliferative capacity of both MKN-45 and MKN-28 cells in a concentration-dependent manner. Lobetyolin reduced the uptake of glutamine and downregulated the expression levels of ASCT2 in GC cells and xenograft tumors. Lobetyolin effectively restrained the growth of tumors in vivo. In addition, lobetyolin induced the accumulation of ROS to attenuate mitochondria-mediated apoptosis via downregulation of ASCT2 expression. Lobetyolin promoted the phosphorylation of c-Myc and suppressed the phosphorylation of GSK3β and AKT in both MKN-45 and MKN-28 cells. The level of total Nrf2 protein was reduced after lobetyolin treatment. Overall, lobetyolin exerts anti-cancer effects by repressing cell proliferation and inducing cell apoptosis via downregulation of ASCT2 in GC.
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Affiliation(s)
- Lin Cheng
- Department of Gastroenterology, The Central Hospital of Qianjiang, Yangtze University, Qianjiang, 433100 China
| | - Haoqing Zhai
- Department of Oncology, The Central Hospital of Qianjiang, Yangtze University, Qianjiang, 433100 China
| | - Juan Du
- Department of Internal Medicine, Hubei University Hospital, Wuhan, 430062 China
| | - Gang Zhang
- Department of Digestive 2, Wuhan Sixth Hospital, Wuhan, 430015 China
| | - Gan Shi
- Department of Gastroenterology, Wuhan Xinzhou District People’s Hospital, No.61, Xinzhou Street, Zhucheng Street, Xinzhou District, Wuhan, 430400 China
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15
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Song X, Liang Y, Zhou S, Xie W, Yang Q, Ma N, Shen X. Glutamine alleviates Lipopolysaccharide-induced corneal epithelial inflammation and oxidative stress in dogs. Exp Eye Res 2023; 234:109607. [PMID: 37517541 DOI: 10.1016/j.exer.2023.109607] [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: 04/18/2023] [Revised: 07/26/2023] [Accepted: 07/27/2023] [Indexed: 08/01/2023]
Abstract
Pseudomonas aeruginosa is a common pathogenic bacteria in canine ophthalmology. Lipopolysaccharide (LPS), a component in the cell wall of gram-negative bacteria, is released following bacterial lysis and causes pathology and inflammation of the cornea. Antibiotics are used to treat bacterial keratitis, and the reuse of antibiotics can easily cause bacterial resistance. Research has shown that glutamine (GLN) has anti-inflammatory and antioxidant biological functions. Herein, we explored the effects and underlying mechanisms of GLN and established an LPS-induced cornea inflammation model. Treatment groups comprised: control check (CK), LPS, LPS + GLN, and Sham groups. Topical GLN treatment alleviated corneal opacity, reduced corneal injury, and accelerated corneal wound healing. Furthermore, GLN treatment altered the uniform distribution of corneal epithelial cells and transformed the healing approach of these cells in the corneal wound from crawling to filling. The expression of Toll-like receptor 4 (TLR4), IL-6, TNF-α, and p-p65 and the activity of myeloperoxidase and superoxide dismutase decreased while the content of malondialdehyde increased in the LPS + GLN group compared with those in the LPS group. Thus, our study suggests that LPS-induced inflammation and oxidative stress may be suppressed via the TLR4/NF-κB signaling pathway by GLN and that GLN could be used as an adjunct therapy to reduce antibiotic use.
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Affiliation(s)
- Xiaokun Song
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China
| | - Yuxuan Liang
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China
| | - Shendong Zhou
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China
| | - Wan Xie
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China
| | - Qifeng Yang
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China
| | - Nana Ma
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China
| | - Xiangzhen Shen
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, PR China.
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16
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Zhang H, Wang X, Ma Y, Zhang Q, Liu R, Luo H, Wang Z. Review of possible mechanisms of radiotherapy resistance in cervical cancer. Front Oncol 2023; 13:1164985. [PMID: 37692844 PMCID: PMC10484717 DOI: 10.3389/fonc.2023.1164985] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 07/31/2023] [Indexed: 09/12/2023] Open
Abstract
Radiotherapy is one of the main treatments for cervical cancer. Early cervical cancer is usually considered postoperative radiotherapy alone. Radiotherapy combined with cisplatin is the standard treatment for locally advanced cervical cancer (LACC), but sometimes the disease will relapse within a short time after the end of treatment. Tumor recurrence is usually related to the inherent radiation resistance of the tumor, mainly involving cell proliferation, apoptosis, DNA repair, tumor microenvironment, tumor metabolism, and stem cells. In the past few decades, the mechanism of radiotherapy resistance of cervical cancer has been extensively studied, but due to its complex process, the specific mechanism of radiotherapy resistance of cervical cancer is still not fully understood. In this review, we discuss the current status of radiotherapy resistance in cervical cancer and the possible mechanisms of radiotherapy resistance, and provide favorable therapeutic targets for improving radiotherapy sensitivity. In conclusion, this article describes the importance of understanding the pathway and target of radioresistance for cervical cancer to promote the development of effective radiotherapy sensitizers.
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Affiliation(s)
- Hanqun Zhang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of Oncology, Guizhou Provincial People's Hospital, Guizhou, China
| | - Xiaohu Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- University of Chinese Academy of Sciences, Beijing, China
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Lanzhou Heavy Ion Hospital, Lanzhou, China
| | - Yan Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Qiuning Zhang
- University of Chinese Academy of Sciences, Beijing, China
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Lanzhou Heavy Ion Hospital, Lanzhou, China
| | - Ruifeng Liu
- University of Chinese Academy of Sciences, Beijing, China
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Lanzhou Heavy Ion Hospital, Lanzhou, China
| | - Hongtao Luo
- University of Chinese Academy of Sciences, Beijing, China
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Lanzhou Heavy Ion Hospital, Lanzhou, China
| | - Zi Wang
- Department of Oncology, Guizhou Provincial People's Hospital, Guizhou, China
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Li S, Pei L, Zhou Q, Fu Z, Zhang L, Liu P, Yan N, Xi S. SLC1A5 regulates cell proliferation and self-renewal through β-catenin pathway mediated by redox signaling in arsenic-treated uroepithelial cells. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 262:115204. [PMID: 37393816 DOI: 10.1016/j.ecoenv.2023.115204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 06/13/2023] [Accepted: 06/27/2023] [Indexed: 07/04/2023]
Abstract
Arsenic exposure increases the risk of bladder cancer in humans, but its underlying mechanisms remain elusive. The alanine, serine, cysteine-preferring transporter 2 (ASCT2, SLC1A5) is frequently overexpressed in cancer cells. The aim of this study was to evaluate the effects of arsenic on SLC1A5, and to determine the role of SLC1A5 in the proliferation and self-renewal of uroepithelial cells. F344 rats were exposed to 87 mg/L NaAsO2 or 200 mg/L DMAV for 12 weeks. The SV-40 immortalized human uroepithelial (SV-HUC-1) cells were cultured in medium containing 0.5 μM NaAsO2 for 40 weeks. Arsenic increased the expression levels of SLC1A5 and β-catenin both in vivo and in vitro. SLC1A5 promoted cell proliferation and self-renewal by activating β-catenin, which in turn was dependent on maintaining GSH/ROS homeostasis. Our results suggest that SLC1A5 is a potential therapeutic target for arsenic-induced proliferation and self-renewal of uroepithelial cells.
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Affiliation(s)
- Sihao Li
- Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China
| | - Liang Pei
- Department of Pediatric, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Qing Zhou
- Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang, Liaoning Province, China
| | - Zhushan Fu
- Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang, Liaoning Province, China
| | - Lei Zhang
- Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang, Liaoning Province, China
| | - Pinya Liu
- Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang, Liaoning Province, China
| | - Nan Yan
- School of Medical Applied Technology, Shenyang Medical College, Shenyang, Liaoning Province, China
| | - Shuhua Xi
- Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China; Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang, Liaoning Province, China; School of Medical Applied Technology, Shenyang Medical College, Shenyang, Liaoning Province, China.
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Glutamine Starvation Affects Cell Cycle, Oxidative Homeostasis and Metabolism in Colorectal Cancer Cells. Antioxidants (Basel) 2023; 12:antiox12030683. [PMID: 36978930 PMCID: PMC10045305 DOI: 10.3390/antiox12030683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/03/2023] [Accepted: 03/08/2023] [Indexed: 03/12/2023] Open
Abstract
Cancer cells adjust their metabolism to meet energy demands. In particular, glutamine addiction represents a distinctive feature of several types of tumors, including colorectal cancer. In this study, four colorectal cancer cell lines (Caco-2, HCT116, HT29 and SW480) were cultured with or without glutamine. The growth and proliferation rate, colony-forming capacity, apoptosis, cell cycle, redox homeostasis and metabolomic analysis were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test (MTT), flow cytometry, high-performance liquid chromatography and gas chromatography/mass spectrometry techniques. The results show that glutamine represents an important metabolite for cell growth and that its deprivation reduces the proliferation of colorectal cancer cells. Glutamine depletion induces cell death and cell cycle arrest in the GO/G1 phase by modulating energy metabolism, the amino acid content and antioxidant defenses. Moreover, the combined glutamine starvation with the glycolysis inhibitor 2-deoxy-D-glucose exerted a stronger cytotoxic effect. This study offers a strong rationale for targeting glutamine metabolism alone or in combination with glucose metabolism to achieve a therapeutic benefit in the treatment of colon cancer.
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Ni R, Li Z, Li L, Peng D, Ming Y, Li L, Liu Y. Rethinking glutamine metabolism and the regulation of glutamine addiction by oncogenes in cancer. Front Oncol 2023; 13:1143798. [PMID: 36959802 PMCID: PMC10029103 DOI: 10.3389/fonc.2023.1143798] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 02/24/2023] [Indexed: 03/09/2023] Open
Abstract
Glutamine, the most abundant non-essential amino acid in human blood, is crucial for cancer cell growth and cancer progression. Glutamine mainly functions as a carbon and nitrogen source for biosynthesis, energy metabolism, and redox homeostasis maintenance in cancer cells. Dysregulated glutamine metabolism is a notable metabolic characteristic of cancer cells. Some carcinogen-driven cancers exhibit a marked dependence on glutamine, also known as glutamine addiction, which has rendered the glutamine metabolic pathway a breakpoint in cancer therapeutics. However, some cancer cells can adapt to the glutamine unavailability by reprogramming metabolism, thus limiting the success of this therapeutic approach. Given the complexity of metabolic networks and the limited impact of inhibiting glutamine metabolism alone, the combination of glutamine metabolism inhibition and other therapeutic methods may outperform corresponding monotherapies in the treatment of cancers. This review summarizes the uptake, transport, and metabolic characteristics of glutamine, as well as the regulation of glutamine dependence by some important oncogenes in various cancers to emphasize the therapeutic potential of targeting glutamine metabolism. Furthermore, we discuss a glutamine metabolic pathway, the glutaminase II pathway, that has been substantially overlooked. Finally, we discuss the applicability of polytherapeutic strategies targeting glutamine metabolism to provide a new perspective on cancer therapeutics.
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Affiliation(s)
- Rui Ni
- Department of pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Ziwei Li
- Department of pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Li Li
- Department of pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Dan Peng
- Department of pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Yue Ming
- Department of pharmacy, Daping Hospital, Army Medical University, Chongqing, China
| | - Lin Li
- Department of pharmacy, Women and Children’s Hospital of Chongqing Medical University, Chongqing Health Center for Women and Children, Chongqing, China
- *Correspondence: Lin Li, ; Yao Liu,
| | - Yao Liu
- Department of pharmacy, Daping Hospital, Army Medical University, Chongqing, China
- *Correspondence: Lin Li, ; Yao Liu,
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Glutamine increases stability of TPH1 mRNA via p38 mitogen-activated kinase in mouse mastocytoma cells. Mol Biol Rep 2023; 50:267-277. [PMID: 36331742 PMCID: PMC9884262 DOI: 10.1007/s11033-022-07693-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 06/07/2022] [Accepted: 06/08/2022] [Indexed: 11/06/2022]
Abstract
Expression changes for tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme in serotonin synthesis, by environmental glutamine (GLN) were examined in mouse mastocytoma-derived P815-HTR cells. GLN-treated cells exhibited a robust increase in TPH1 mRNA after a 6 h exposure to GLN. 6-Diazo-5-oxo-L-norleucine (DON), a glutamine-utilizing glutaminase inhibitor, significantly inhibited the GLN-induction of TPH1 mRNA. Nuclear run-on assays and mRNA decay experiments demonstrated that the primary mechanism leading to increased TPH1 mRNA levels was not due to transcriptional changes, but rather due to increased TPH1 RNA stability induced by GLN. Treatment with GLN also led to activation of p38 MAP kinase, but not p42/44 MAPK. In addition, SB203580, a p38 MAP kinase specific inhibitor, completely abolished the GLN-mediated increase of TPH1 mRNA levels, suggesting the pathway stabilizing TPH1 mRNA might be mediated by the activated p38 MAP kinase pathway. Additionally, SB203580 significantly reduced the stability of TPH1 mRNA, and this reduction of the stability was not affected by GLN in the culture medium, implying a sequential signaling from GLN being mediated by p38 MAP kinase, resulting in alteration of TPH1 mRNA stability. TPH1 mRNA stability loss was also dependent on de novo protein synthesis as shown by treatment of cells with a transcriptional/translational blocker. We provide evidence that TPH1 mRNA levels are increased in response to increased exogenous GLN in mouse mastocytoma cells via a stabilization of TPH1 mRNA due to the activity of the p38 MAP kinase.
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Xu K, Ding J, Zhou L, Li D, Luo J, Wang W, Shang M, Lin B, Zhou L, Zheng S. SMYD2 Promotes Hepatocellular Carcinoma Progression by Reprogramming Glutamine Metabolism via c-Myc/GLS1 Axis. Cells 2022; 12:cells12010025. [PMID: 36611819 PMCID: PMC9818721 DOI: 10.3390/cells12010025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/11/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Metabolic reprogramming, such as alterations in glutamine metabolism or glycolysis, is the hallmark of hepatocellular carcinoma (HCC). However, the underlying mechanisms are still incompletely elucidated. Previous studies have identified that methyltransferase SET and MYND domain-containing protein 2(SMYD2) is responsible for the pathogenesis of numerous types of cancer. Here, we innovatively uncover how SMYD2 regulates glutamine metabolism in HCC cells and promotes HCC progression. We identified that SMYD2 expression is upregulated in HCC tissues, which correlates with unfavorable clinical outcomes. Our in vitro and in vivo results showed that the depletion of SMYD2 inhibits HCC cell growth. Mechanistically, c-Myc methylation by SMYD2 increases its protein stability through the ubiquitin-proteasome system. We showed SMYD2 depletion destabilized c-Myc protein by increasing the conjugated K48-linked polyubiquitin chain. SMYD2 increased c-Myc expression and further upregulated glutaminase1 (GLS1), a crucial enzyme that catalyzes the conversion of glutamine to glutamic acid, in HCC cells. GLS1 plays an important role in SMYD2-mediated HCC progression and glutamine metabolism regulation. The knockdown of SMYD2 inhibited glutamine metabolism in HCC cells and overcame their chemoresistance to sorafenib. Collectively, our findings demonstrated a novel mechanism of how SMYD2 promotes HCC progression by regulating glutamine metabolism through the c-Myc/GLS1signaling, implicating the therapeutic potential of targeting SMYD2 in HCC patients.
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Affiliation(s)
- Kangdi Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, NO.79 Qing Chun Road, Hangzhou 310006, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Jun Ding
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, NO.79 Qing Chun Road, Hangzhou 310006, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Lingfeng Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, NO.79 Qing Chun Road, Hangzhou 310006, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Dazhi Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, NO.79 Qing Chun Road, Hangzhou 310006, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Jia Luo
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, NO.79 Qing Chun Road, Hangzhou 310006, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Wenchao Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, NO.79 Qing Chun Road, Hangzhou 310006, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Mingge Shang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, NO.79 Qing Chun Road, Hangzhou 310006, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Bingyi Lin
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, NO.79 Qing Chun Road, Hangzhou 310006, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, NO.79 Qing Chun Road, Hangzhou 310006, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
- Correspondence: (L.Z.); (S.Z.); Tel.: +86-0571-87236466 (L.Z.); +86-0571-87236570 (S.Z.)
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, NO.79 Qing Chun Road, Hangzhou 310006, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou 310003, China
- Correspondence: (L.Z.); (S.Z.); Tel.: +86-0571-87236466 (L.Z.); +86-0571-87236570 (S.Z.)
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22
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Lacticaseibacillus rhamnosus Probio-M9-Driven Mouse Mammary Tumor-Inhibitory Effect Is Accompanied by Modulation of Host Gut Microbiota, Immunity, and Serum Metabolome. Nutrients 2022; 15:nu15010005. [PMID: 36615662 PMCID: PMC9824041 DOI: 10.3390/nu15010005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/10/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
Gut microbiome may influence tumor growth and cancer treatment efficacy, so it is a potential target for tumor prevention/treatment. This pilot study investigated the preventive and therapeutic effects of a probiotic strain, Lacticaseibacillus rhamnosus Probio-M9 (Probio-M9), against murine mammary cancer. Thirty-six female mice were randomly divided into three groups (n = 12 per group): control (without tumor transplantation), model (tumor transplantation; no probiotic administration), and probiotic (30-day oral gavage of probiotic, started seven days before tumor transplantation). Changes in tumor size were recorded, and blood, tumor tissue, and stool samples were collected at the end of the trial for analyses. Comparing with the model group, the probiotic group had a significantly smaller tumor volume (p < 0.05), a higher fecal microbiota Shannon diversity index, with significant modifications in the gut microbiota structure (p < 0.05), characterized by more Alistipes sp._2, Porphyromonadaceae bacterium_7, and Bacteroidales bacterium 55_9 (p < 0.05). Additionally, Probio-M9 administration elevated the serum IFN-γ, IL-9, IL-13, and IL-27 levels and several metabolites (e.g., pyridoxal, nicotinic acid, 3-hydroxybutyric acid, glutamine; p < 0.05), while reducing IL-5 (p < 0.05). These changes might be associated with the protective effect of Probio-M9 against mammary tumor growth. Thus, probiotic administration could harness host gut microbiome in anti-cancer responses.
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23
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Liu H, Zhang B, Li F, Liu L, Yang T, Zhang H, Li F. Effects of heat stress on growth performance, carcass traits, serum metabolism, and intestinal microflora of meat rabbits. Front Microbiol 2022; 13:998095. [PMID: 36519173 PMCID: PMC9743647 DOI: 10.3389/fmicb.2022.998095] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 10/04/2022] [Indexed: 07/30/2023] Open
Abstract
To investigate the effects of heat stress on meat rabbits, we assigned 80 rabbits to the moderate temperature group (24 ± 1°C; Control group) and the continuous high-temperature group (HT group), then monitored the effects using growth performance, carcass characteristics, biochemical assays, UPLC-MS/MS-based metabolomics, and microbiome. The results showed that after continuous high-temperature exposure, the average daily gain, average daily feed intake, and thymus index were significantly decreased (p < 0.05). Contents of HSP70, ALP, and Cortisol in serum were significantly increased, while TP, GLU, T3, and T4 were significantly decreased (p < 0.05). Nine kinds of differential metabolites were screened by serum metabolomics, which can be used as biomarkers of heat stress in meat rabbits. The selected differential metabolites were analyzed by KEGG annotation and enrichment analysis. The results showed that 14 pathways affected by heat stress were identified by KEGG pathway enrichment analysis, including Sphingolipid metabolism, Pyrimidine metabolism, Citrate cycle (TCA cycle)), aminoacyl-tRNA biosynthesis, and so on. The analysis of the effect of heat stress on the cecal microflora of meat rabbits showed that the abundance of cecal Proteus in the HT group was significantly higher than that in the moderate Control group. The number of Candidatus-saccharimonas in the cecum microflora was significantly higher than that in the moderate temperature group (p < 0.05) which may be related to inflammatory diseases in the heat stress group. These findings indicated that the heat-stressed rabbits were in negative energy balance, which affected protein metabolism, and subsequently affected growth performance and carcass characteristics.
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Affiliation(s)
- Hongli Liu
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Technology, Shandong Agricultural University, Taian, Shandong, China
- Hebei Key Laboratory of Specialty Animal Germplasm Resources Exploration and Innovation, Department of Animal Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, Hebei, China
| | - Bin Zhang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Technology, Shandong Agricultural University, Taian, Shandong, China
| | - Fan Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Technology, Shandong Agricultural University, Taian, Shandong, China
| | - Lei Liu
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Technology, Shandong Agricultural University, Taian, Shandong, China
| | - Tongao Yang
- Hebei Key Laboratory of Specialty Animal Germplasm Resources Exploration and Innovation, Department of Animal Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, Hebei, China
| | - Haihua Zhang
- Hebei Key Laboratory of Specialty Animal Germplasm Resources Exploration and Innovation, Department of Animal Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, Hebei, China
| | - Fuchang Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Science and Technology, Shandong Agricultural University, Taian, Shandong, China
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Zhou J, Lei N, Tian W, Guo R, Chen M, Qiu L, Wu F, Li Y, Chang L. Recent progress of the tumor microenvironmental metabolism in cervical cancer radioresistance. Front Oncol 2022; 12:999643. [PMID: 36313645 PMCID: PMC9597614 DOI: 10.3389/fonc.2022.999643] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 09/27/2022] [Indexed: 08/01/2023] Open
Abstract
Radiotherapy is widely used as an indispensable treatment option for cervical cancer patients. However, radioresistance always occurs and has become a big obstacle to treatment efficacy. The reason for radioresistance is mainly attributed to the high repair ability of tumor cells that overcome the DNA damage caused by radiotherapy, and the increased self-healing ability of cancer stem cells (CSCs). Accumulating findings have demonstrated that the tumor microenvironment (TME) is closely related to cervical cancer radioresistance in many aspects, especially in the metabolic processes. In this review, we discuss radiotherapy in cervical cancer radioresistance, and focus on recent research progress of the TME metabolism that affects radioresistance in cervical cancer. Understanding the mechanism of metabolism in cervical cancer radioresistance may help identify useful therapeutic targets for developing novel therapy, overcome radioresistance and improve the efficacy of radiotherapy in clinics and quality of life of patients.
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Affiliation(s)
- Junying Zhou
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ningjing Lei
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Wanjia Tian
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ruixia Guo
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mengyu Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Luojie Qiu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Fengling Wu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yong Li
- Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia
- St George and Sutherland Clinical Campuses, School of Clinical Medicine, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
| | - Lei Chang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Hydroxyapatite Biobased Materials for Treatment and Diagnosis of Cancer. Int J Mol Sci 2022; 23:ijms231911352. [PMID: 36232652 PMCID: PMC9569977 DOI: 10.3390/ijms231911352] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/19/2022] [Accepted: 09/21/2022] [Indexed: 11/22/2022] Open
Abstract
Great advances in cancer treatment have been undertaken in the last years as a consequence of the development of new antitumoral drugs able to target cancer cells with decreasing side effects and a better understanding of the behavior of neoplastic cells during invasion and metastasis. Specifically, drug delivery systems (DDS) based on the use of hydroxyapatite nanoparticles (HAp NPs) are gaining attention and merit a comprehensive review focused on their potential applications. These are derived from the intrinsic properties of HAp (e.g., biocompatibility and biodegradability), together with the easy functionalization and easy control of porosity, crystallinity and morphology of HAp NPs. The capacity to tailor the properties of DLS based on HAp NPs has well-recognized advantages for the control of both drug loading and release. Furthermore, the functionalization of NPs allows a targeted uptake in tumoral cells while their rapid elimination by the reticuloendothelial system (RES) can be avoided. Advances in HAp NPs involve not only their use as drug nanocarriers but also their employment as nanosystems for magnetic hyperthermia therapy, gene delivery systems, adjuvants for cancer immunotherapy and nanoparticles for cell imaging.
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26
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Suriya Muthukumaran N, Velusamy P, Akino Mercy CS, Langford D, Natarajaseenivasan K, Shanmughapriya S. MicroRNAs as Regulators of Cancer Cell Energy Metabolism. J Pers Med 2022; 12:1329. [PMID: 36013278 PMCID: PMC9410355 DOI: 10.3390/jpm12081329] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/11/2022] [Accepted: 08/16/2022] [Indexed: 11/17/2022] Open
Abstract
To adapt to the tumor environment or to escape chemotherapy, cancer cells rapidly reprogram their metabolism. The hallmark biochemical phenotype of cancer cells is the shift in metabolic reprogramming towards aerobic glycolysis. It was thought that this metabolic shift to glycolysis alone was sufficient for cancer cells to meet their heightened energy and metabolic demands for proliferation and survival. Recent studies, however, show that cancer cells rely on glutamine, lipid, and mitochondrial metabolism for energy. Oncogenes and scavenging pathways control many of these metabolic changes, and several metabolic and tumorigenic pathways are post-transcriptionally regulated by microRNA (miRNAs). Genes that are directly or indirectly responsible for energy production in cells are either negatively or positively regulated by miRNAs. Therefore, some miRNAs play an oncogenic role by regulating the metabolic shift that occurs in cancer cells. Additionally, miRNAs can regulate mitochondrial calcium stores and energy metabolism, thus promoting cancer cell survival, cell growth, and metastasis. In the electron transport chain (ETC), miRNAs enhance the activity of apoptosis-inducing factor (AIF) and cytochrome c, and these apoptosome proteins are directed towards the ETC rather than to the apoptotic pathway. This review will highlight how miRNAs regulate the enzymes, signaling pathways, and transcription factors of cancer cell metabolism and mitochondrial calcium import/export pathways. The review will also focus on the metabolic reprogramming of cancer cells to promote survival, proliferation, growth, and metastasis with an emphasis on the therapeutic potential of miRNAs for cancer treatment.
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Affiliation(s)
| | - Prema Velusamy
- Heart and Vascular Institute, Department of Medicine, Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Dauphin, PA 17033, USA
| | - Charles Solomon Akino Mercy
- Medical Microbiology Laboratory, Department of Microbiology, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India
| | - Dianne Langford
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Kalimuthusamy Natarajaseenivasan
- Medical Microbiology Laboratory, Department of Microbiology, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Santhanam Shanmughapriya
- Heart and Vascular Institute, Department of Medicine, Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Dauphin, PA 17033, USA
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Holzknecht M, Guerrero‐Navarro L, Petit M, Albertini E, Damisch E, Simonini A, Schmitt F, Parson W, Fiegl H, Weiss A, Jansen‐Duerr P. The mitochondrial enzyme
FAHD1
regulates complex
II
activity in breast cancer cells and is indispensable for basal
BT
‐20 cells
in vitro. FEBS Lett 2022; 596:2781-2794. [DOI: 10.1002/1873-3468.14462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/29/2022] [Accepted: 06/30/2022] [Indexed: 11/08/2022]
Affiliation(s)
- Max Holzknecht
- Leopold‐Franzens University of Innsbruck Institute for Biomedical Aging Research Rennweg 10 6020 Innsbruck Austria
| | - Lena Guerrero‐Navarro
- Leopold‐Franzens University of Innsbruck Institute for Biomedical Aging Research Rennweg 10 6020 Innsbruck Austria
| | - Michele Petit
- Leopold‐Franzens University of Innsbruck Institute for Biomedical Aging Research Rennweg 10 6020 Innsbruck Austria
| | - Eva Albertini
- Leopold‐Franzens University of Innsbruck Institute for Biomedical Aging Research Rennweg 10 6020 Innsbruck Austria
| | - Elisabeth Damisch
- Leopold‐Franzens University of Innsbruck Institute for Biomedical Aging Research Rennweg 10 6020 Innsbruck Austria
| | - Anna Simonini
- Leopold‐Franzens University of Innsbruck Institute for Biomedical Aging Research Rennweg 10 6020 Innsbruck Austria
| | - Fernando Schmitt
- Medical Faculty of University of Porto CINTESIS@RISE (Health Research Network), Alameda Prof. Hernâni Monteiro 4200‐319 Porto Portugal
| | - Walther Parson
- Institute of Legal Medicine Medical University of Innsbruck 6020 Innsbruck Austria
- Forensic Science Program, The Pennsylvania State University University Park PA 16801 USA
| | - Heidelinde Fiegl
- Medical University of Innsbruck, Department of Obstetrics and Gynaecology Anichstraße 35 6020 Innsbruck Austria
| | - Alexander Weiss
- Leopold‐Franzens University of Innsbruck Institute for Biomedical Aging Research Rennweg 10 6020 Innsbruck Austria
| | - Pidder Jansen‐Duerr
- Leopold‐Franzens University of Innsbruck Institute for Biomedical Aging Research Rennweg 10 6020 Innsbruck Austria
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[18F]-(2S,4R)4-Fluoroglutamine PET Imaging of Glutamine Metabolism in Murine Models of Hepatocellular Carcinoma (HCC). Mol Imaging 2022; 2022:5185951. [PMID: 35967756 PMCID: PMC9351703 DOI: 10.1155/2022/5185951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/01/2022] [Accepted: 07/06/2022] [Indexed: 11/18/2022] Open
Abstract
Purpose Quantitative in vivo [18F]-(2S,4R)4-fluoroglutamine ([18F]4-FGln or more simply [18F]FGln) metabolic kinetic parameters are compared with activity levels of glutamine metabolism in different types of hepatocellular carcinoma (HCC). Methods For this study, we used two transgenic mouse models of HCC induced by protooncogenes, MYC, and MET. Biochemical data have shown that tumors induced by MYC have increased levels of glutamine metabolism compared to those induced by MET. One-hour dynamic [18F]FGln PET data were acquired and reconstructed for fasted MYC mice (n = 11 tumors from 7 animals), fasted MET mice (n = 8 tumors from 6 animals), fasted FVBN controls (n = 8 normal liver regions from 6 animals), nonfasted MYC mice (n = 16 tumors from 6 animals), and nonfasted FVBN controls (n = 8 normal liver regions from 3 animals). The influx rate constants (K1) using the one-tissue compartment model were derived for each tumor with the left ventricular blood pool input function. Results Influx rate constants were significantly higher for MYC tumors (K1 = 0.374 ± 0.133) than for MET tumors (K1 = 0.141 ± 0.058) under fasting conditions (P = 0.0002). Rate constants were also significantly lower for MET tumors (K1 = 0.141 ± 0.135) than normal livers (K1 = 0.332 ± 0.179) under fasting conditions (P = 0.0123). Fasting conditions tested for MYC tumors and normal livers did not result in any significant difference with P values > 0.005. Conclusion Higher influx rate constants corresponded to elevated levels of glutamine metabolism as determined by biochemical assays. The data showed that there is a distinctive difference in glutamine metabolism between MYC and MET tumors. Our study has demonstrated the potential of [18F]FGln PET imaging as a tool to assess glutamine metabolism in HCC tumors in vivo with a caution that it may not be able to clearly distinguish HCC tumors from normal liver tissue.
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Targeting metabolic reprogramming in chronic lymphocytic leukemia. Exp Hematol Oncol 2022; 11:39. [PMID: 35761419 PMCID: PMC9235173 DOI: 10.1186/s40164-022-00292-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 06/05/2022] [Indexed: 11/28/2022] Open
Abstract
Metabolic reprogramming, fundamentally pivotal in carcinogenesis and progression of cancer, is considered as a promising therapeutic target against tumors. In chronic lymphocytic leukemia (CLL) cells, metabolic abnormalities mediate alternations in proliferation and survival compared with normal B cells. However, the role of metabolic reprogramming is still under investigation in CLL. In this review, the critical metabolic processes of CLL were summarized, particularly glycolysis, lipid metabolism and oxidative phosphorylation. The effects of T cells and stromal cells in the microenvironment on metabolism of CLL were also elucidated. Besides, the metabolic alternation is regulated by some oncogenes and tumor suppressor regulators, especially TP53, MYC and ATM. Thus, the agents targeting metabolic enzymes or signal pathways may impede the progression of CLL. Both the inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) statins and the lipoprotein lipase inhibitor orlistat induce the apoptosis of CLL cells. In addition, a series of oxidative phosphorylation inhibitors play important roles in decreasing the proliferation of CLL cells. We epitomized recent advancements in metabolic reprogramming in CLL and discussed their clinical potentiality for innovative therapy options. Metabolic reprogramming plays a vital role in the initiation and progression of CLL. Therapeutic approaches targeting metabolism have their advantages in improving the survival of CLL patients. This review may shed novel light on the metabolism of CLL, leading to the development of targeted agents based on the reshaping metabolism of CLL cells.
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Wang L, Zhou C, Sun J, Zhang Q, Lai D. Glutamine and norepinephrine in follicular fluid synergistically enhance the antioxidant capacity of human granulosa cells and the outcome of IVF-ET. Sci Rep 2022; 12:9936. [PMID: 35705692 PMCID: PMC9200745 DOI: 10.1038/s41598-022-14201-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 06/02/2022] [Indexed: 11/09/2022] Open
Abstract
An increasing number of studies demonstrate that changes in neurotransmitters metabolic levels in follicular fluid are directly related to oocyte maturation, fertilization, the quality of embryo and pregnancy rates. However, the relationship between the intra-follicular neurotransmitters and the function of granulosa cells (GCs), and the outcome of in vitro fertilization-embryo transfer (IVF-ET) is not clear. Human follicular fluid and cumulus GCs were harvested from large follicles obtained from patients undergoing IVF. Neurotransmitters and steroid hormones in follicular fluid were measured through liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). Based on the content of glutamine (Gln) in follicular fluid, the samples were divided into two groups: high Gln level group and low Gln level group. The expression of proliferation-, steroidogenesis- and antioxidant-related genes in GCs was detected by qRT-PCR. In vitro, KGN cells were used to further verify the effects of Gln and NE on GCs function. Primary and secondary outcomes were the number of mature and retrieved oocytes, and the ratio of high-quality embryos, respectively. Gln (46.75 ± 7.74 μg/mL) and norepinephrine (NE, 0.20 ± 0.07 μg/mL) were abundant neurotransmitters in follicular fluid, and exhibited a significantly positive correlation (R = 0.5869, P < 0.005). In high Gln level group, the expression of proliferation, steroidogenesis and antioxidant-related genes in GCs were higher than those in low Gln level group, and the contents of estriol and E2 in follicular fluid were more abundant. Moreover, the concentrations of Gln and NE in follicular fluid showed significantly positive correlation with IDH1 expression in GCs (R = 0.3822, R = 0.4009, P < 0.05). Importantly, a significantly positive correlation was observed between IDH1 expression in GCs and the ratio of higher-quality/cleaved embryos (R = 0.4480, P < 0.05). In vitro studies further demonstrated that Gln and NE played synergistically function in improving GCs proliferation and E2 production by upregulating IDH1 expression. These data demonstrate that Gln and NE in follicular fluid might play significant positive roles in GCs function, and may be potential predictors for selecting optimal quality oocytes and evaluating the quality of embryonic development.
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Affiliation(s)
- Lulu Wang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, 145, Guang-Yuan Road, Shanghai, 200030, China
| | - Chengliang Zhou
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, 145, Guang-Yuan Road, Shanghai, 200030, China
| | - Junyan Sun
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, 145, Guang-Yuan Road, Shanghai, 200030, China
| | - Qiuwan Zhang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, 145, Guang-Yuan Road, Shanghai, 200030, China. .,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China.
| | - Dongmei Lai
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, 145, Guang-Yuan Road, Shanghai, 200030, China. .,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China.
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Yang Y, Zheng M, Han F, Shang L, Li M, Gu X, Li H, Chen L. Ziprasidone suppresses pancreatic adenocarcinoma cell proliferation by targeting GOT1 to trigger glutamine metabolism reprogramming. J Mol Med (Berl) 2022; 100:599-612. [PMID: 35212782 DOI: 10.1007/s00109-022-02181-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 02/10/2022] [Accepted: 02/14/2022] [Indexed: 11/30/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignant tumor whose effective treatment has not been found. The redox state and proliferative activity of PDAC cells are maintained by the conversion of aspartic acid in the cytoplasm into oxaloacetate though aspartate aminotransferase 1 (GOT1). Therefore, GOT1 inhibitors as a potential approach for treating PDAC have attracted more attention of researchers. Ziprasidone effectively inhibited GOT1 in a non-competitive manner. The potential cytotoxicity and anti-proliferation effects of ziprasidone against PDAC cells in vitro and in vivo were evaluated. Ziprasidone can induce glutamine metabolism disorder and redox state imbalance of PDAC cells by targeting GOT1, thereby inhibiting proliferation, preventing migration, and inducing apoptosis. Ziprasidone displayed significant in vivo antitumor efficacy in SW1990 cell-derived xenografts. What's more, knockdown of GOT1 in SW1990 reduced the anti-proliferative effects of ziprasidone. As a novel GOT1 inhibitor, ziprasidone may be a lead compound for the treatment of PDAC. KEY MESSAGES: Small molecule inhibitors targeting GOT1 may provide a therapeutic target in PDAC. Ziprasidone effectively inhibited GOT1 enzyme in a non-competitive manner. Ziprasidone repressed glutamine metabolism and inhibited the growth of tumor in vivo. Knockdown of GOT1 decreased the anti-proliferative effects of ziprasidone.
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Affiliation(s)
- Yueying Yang
- Wuya College of Innovation, School of Pharmacy, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Mengzhu Zheng
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Fei Han
- Wuya College of Innovation, School of Pharmacy, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Lei Shang
- School of Pharmacy, Shenyang Medical College, Shenyang, 110034, China
| | - Mingxue Li
- Wuya College of Innovation, School of Pharmacy, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Xiaoxia Gu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Hua Li
- Wuya College of Innovation, School of Pharmacy, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Lixia Chen
- Wuya College of Innovation, School of Pharmacy, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
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Upregulation of Yin-Yang-1 Associates with Proliferation and Glutamine Metabolism in Esophageal Carcinoma. Int J Genomics 2022; 2022:9305081. [PMID: 35359580 PMCID: PMC8961439 DOI: 10.1155/2022/9305081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 03/04/2022] [Indexed: 12/24/2022] Open
Abstract
Objective To investigate the expression of Yin-Yang-1 (YY1) in esophageal carcinoma (ESCA) and its effect on glutamine metabolism in ESCA. Methods The expression and roles of YY1 in ESCA were investigated using a series of bioinformatics databases and tools. The expression of YY1 between ESCA tissues with the corresponding adjacent tissues was validated using real-time PCR, western blot, and immunohistochemical staining method. Furthermore, the effects of YY1 on ESCC cell proliferation and migration were examined. The correlation between the YY1 and glutamine metabolism was evaluated by western blot. Results YY1 gene was highly conserved in evolution and upregulated in ESCA tissues and ESCC cell lines (ECA109 and TE-1). In addition, YY1 may affect the level of immune cell infiltration and promote tumor cell immune escape. Functional enrichment analysis found that YY1 involved in many biological processes, such as cell division and glutathione and glutamine metabolism. After siRNA knockdown of YY1 in ECA109 and TE-1, the proliferation and the migration of ECA109 and TE-1 were suppressed. The glutamine consumption and glutamate production were significantly decreased. The protein expression of alanine-, serine-, cysteine-preferring transporter 2 (ASCT2), glutaminase (GLS), and glutamate dehydrogenase (GLUD1) was significantly downregulated. Conclusion YY1 is highly expressed in ESCA and may promote glutamine metabolism of ESCC cells, indicating it may be as a diagnostic biomarker for ESCA.
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Gyamfi J, Kim J, Choi J. Cancer as a Metabolic Disorder. Int J Mol Sci 2022; 23:ijms23031155. [PMID: 35163079 PMCID: PMC8835572 DOI: 10.3390/ijms23031155] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/19/2022] [Accepted: 01/19/2022] [Indexed: 02/08/2023] Open
Abstract
Cancer has long been considered a genetic disease characterized by a myriad of mutations that drive cancer progression. Recent accumulating evidence indicates that the dysregulated metabolism in cancer cells is more than a hallmark of cancer but may be the underlying cause of the tumor. Most of the well-characterized oncogenes or tumor suppressor genes function to sustain the altered metabolic state in cancer. Here, we review evidence supporting the altered metabolic state in cancer including key alterations in glucose, glutamine, and fatty acid metabolism. Unlike genetic alterations that do not occur in all cancer types, metabolic alterations are more common among cancer subtypes and across cancers. Recognizing cancer as a metabolic disorder could unravel key diagnostic and treatments markers that can impact approaches used in cancer management.
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Affiliation(s)
- Jones Gyamfi
- Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Veritas Hall D 306, 85 Songdogwahak-ro, Incheon 21983, Korea; (J.G.); (J.K.)
- Department of Medical Laboratory Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Jinyoung Kim
- Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Veritas Hall D 306, 85 Songdogwahak-ro, Incheon 21983, Korea; (J.G.); (J.K.)
| | - Junjeong Choi
- Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Veritas Hall D 306, 85 Songdogwahak-ro, Incheon 21983, Korea; (J.G.); (J.K.)
- Correspondence: ; Tel.: +82-32-749-4521; Fax: +82-32-749-4105
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Corchado-Cobos R, García-Sancha N, Mendiburu-Eliçabe M, Gómez-Vecino A, Jiménez-Navas A, Pérez-Baena MJ, Holgado-Madruga M, Mao JH, Cañueto J, Castillo-Lluva S, Pérez-Losada J. Pathophysiological Integration of Metabolic Reprogramming in Breast Cancer. Cancers (Basel) 2022; 14:322. [PMID: 35053485 PMCID: PMC8773662 DOI: 10.3390/cancers14020322] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 01/03/2022] [Accepted: 01/06/2022] [Indexed: 02/04/2023] Open
Abstract
Metabolic changes that facilitate tumor growth are one of the hallmarks of cancer. The triggers of these metabolic changes are located in the tumor parenchymal cells, where oncogenic mutations induce an imperative need to proliferate and cause tumor initiation and progression. Cancer cells undergo significant metabolic reorganization during disease progression that is tailored to their energy demands and fluctuating environmental conditions. Oxidative stress plays an essential role as a trigger under such conditions. These metabolic changes are the consequence of the interaction between tumor cells and stromal myofibroblasts. The metabolic changes in tumor cells include protein anabolism and the synthesis of cell membranes and nucleic acids, which all facilitate cell proliferation. They are linked to catabolism and autophagy in stromal myofibroblasts, causing the release of nutrients for the cells of the tumor parenchyma. Metabolic changes lead to an interstitium deficient in nutrients, such as glucose and amino acids, and acidification by lactic acid. Together with hypoxia, they produce functional changes in other cells of the tumor stroma, such as many immune subpopulations and endothelial cells, which lead to tumor growth. Thus, immune cells favor tissue growth through changes in immunosuppression. This review considers some of the metabolic changes described in breast cancer.
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Affiliation(s)
- Roberto Corchado-Cobos
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (R.C.-C.); (N.G.-S.); (M.M.-E.); (A.G.-V.); (A.J.-N.); (M.J.P.-B.); (J.C.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Natalia García-Sancha
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (R.C.-C.); (N.G.-S.); (M.M.-E.); (A.G.-V.); (A.J.-N.); (M.J.P.-B.); (J.C.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Marina Mendiburu-Eliçabe
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (R.C.-C.); (N.G.-S.); (M.M.-E.); (A.G.-V.); (A.J.-N.); (M.J.P.-B.); (J.C.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Aurora Gómez-Vecino
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (R.C.-C.); (N.G.-S.); (M.M.-E.); (A.G.-V.); (A.J.-N.); (M.J.P.-B.); (J.C.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Alejandro Jiménez-Navas
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (R.C.-C.); (N.G.-S.); (M.M.-E.); (A.G.-V.); (A.J.-N.); (M.J.P.-B.); (J.C.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Manuel Jesús Pérez-Baena
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (R.C.-C.); (N.G.-S.); (M.M.-E.); (A.G.-V.); (A.J.-N.); (M.J.P.-B.); (J.C.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Marina Holgado-Madruga
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
- Departamento de Fisiología y Farmacología, Universidad de Salamanca, 37007 Salamanca, Spain
- Instituto de Neurociencias de Castilla y León (INCyL), Universidad de Salamanca, 37007 Salamanca, Spain
| | - Jian-Hua Mao
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA;
- Berkeley Biomedical Data Science Center, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Javier Cañueto
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (R.C.-C.); (N.G.-S.); (M.M.-E.); (A.G.-V.); (A.J.-N.); (M.J.P.-B.); (J.C.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
- Departamento de Dermatología, Hospital Universitario de Salamanca, Paseo de San Vicente 58-182, 37007 Salamanca, Spain
- Complejo Asistencial Universitario de Salamanca, 37007 Salamanca, Spain
| | - Sonia Castillo-Lluva
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas, Universidad Complutense, 28040 Madrid, Spain
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain
| | - Jesús Pérez-Losada
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain; (R.C.-C.); (N.G.-S.); (M.M.-E.); (A.G.-V.); (A.J.-N.); (M.J.P.-B.); (J.C.)
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain;
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Silverman RB. Inactivators of Ornithine Aminotransferase for the Treatment of Hepatocellular Carcinoma. ACS Med Chem Lett 2021; 13:38-49. [PMID: 35059122 PMCID: PMC8762738 DOI: 10.1021/acsmedchemlett.1c00526] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 11/22/2021] [Indexed: 01/16/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second or third leading cause of cancer mortality worldwide (depending on which statistics are used), yet there is no effective treatment. Currently, there are nine FDA-approved drugs for HCC, five monoclonal antibodies and four tyrosine kinase inhibitors. Ornithine aminotransferase (OAT) has been validated as a target in preclinical studies, which demonstrates that it is a potential target to treat HCC. Currently, there are no OAT inactivators in clinical trials for HCC. This Innovation describes evidence to support inhibition of OAT as a novel approach for HCC tumor growth inhibition. After the mechanism of OAT is discussed, the origins of our involvement in OAT inactivation, based on our previous work on mechanism-based inactivation of GABA-AT, are described. Once it was demonstrated that OAT inactivation does lead to HCC tumor growth inhibition, new selective OAT inactivators were designed and their inactivation mechanisms were elucidated. A summary of these mechanistic studies is presented. Inactivators of OAT provide the potential for treatment of HCC, targeting the Wnt/β-catenin pathway.
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Wang L, Zhao X, Fu J, Xu W, Yuan J. The Role of Tumour Metabolism in Cisplatin Resistance. Front Mol Biosci 2021; 8:691795. [PMID: 34250022 PMCID: PMC8261055 DOI: 10.3389/fmolb.2021.691795] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/10/2021] [Indexed: 12/18/2022] Open
Abstract
Cisplatin is a chemotherapy drug commonly used in cancer treatment. Tumour cells are more sensitive to cisplatin than normal cells. Cisplatin exerts an antitumour effect by interfering with DNA replication and transcription processes. However, the drug-resistance properties of tumour cells often cause loss of cisplatin efficacy and failure of chemotherapy, leading to tumour progression. Owing to the large amounts of energy and compounds required by tumour cells, metabolic reprogramming plays an important part in the occurrence and development of tumours. The interplay between DNA damage repair and metabolism also has an effect on cisplatin resistance; the molecular changes to glucose metabolism, amino acid metabolism, lipid metabolism, and other metabolic pathways affect the cisplatin resistance of tumour cells. Here, we review the mechanism of action of cisplatin, the mechanism of resistance to cisplatin, the role of metabolic remodelling in tumorigenesis and development, and the effects of common metabolic pathways on cisplatin resistance.
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Affiliation(s)
- Lude Wang
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Xiaoya Zhao
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Jianfei Fu
- Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Wenxia Xu
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Jianlie Yuan
- Department of Neurosurgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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Chen Y, Tian Y, Jin G, Cui Z, Guo W, Zhang X, Liu X. Lobetyolin inhibits the proliferation of breast cancer cells via ASCT2 down-regulation-induced apoptosis. Hum Exp Toxicol 2021; 40:2074-2086. [PMID: 34075790 DOI: 10.1177/09603271211021476] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
This study aimed to investigate the anti-cancer effect of lobetyolin on breast cancer cells. Lobetyolin was incubated with MDA-MB-231 and MDA-MB-468 breast cancer cells for 24 h. Glucose uptake and the mRNA expression of GLUT4 (SLC2A4), HK2 and PKM2 were detected to assess the effect of lobetyolin on glucose metabolism. Glutamine uptake and the mRNA expression of ASCT2 (SLC1A5), GLS1, GDH and GLUL were measured to assess the effect of lobetyolin on glutamine metabolism. Annexin V/PI double staining and Hoechst 33342 staining were used to investigate the effect of lobetyolin on cell apoptosis. Immunoblot was employed to estimate the effect of lobetyolin on the expression of proliferation-related markers and apoptosis-related markers. SLC1A5 knockdown with specific siRNA was performed to study the role of ASCT2 played in the anti-cancer effect of lobetyolin on MDA-MB-231 and MDA-MB-468 breast cancer cells. C-MYC knockdown with specific siRNA was performed to study the role of c-Myc played in lobetyolin-induced ASCT2 down-regulation. Myr-AKT overexpression was performed to investigate the role of AKT/GSK3β signaling played in lobetyolin-induced down-regulation of c-Myc and ASCT2. The results showed that lobetyolin inhibited the proliferation of both MDA-MB-231 and MDA-MB-468 breast cancer cells. Lobetyolin disrupted glutamine uptake via down-regulating ASCT2. SLC1A5 knockdown attenuated the anti-cancer effect of lobetyolin. C-MYC knockdown attenuated lobetyolin-caused down-regulation of ASCT2 and Myr-AKT overexpression reversed lobetyolin-caused down-regulation of both c-Myc and ASCT2. In conclusion, the present work suggested that lobetyolin exerted anti-cancer effect via ASCT2 down-regulation-induced apoptosis in breast cancer cells.
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Affiliation(s)
- Yansong Chen
- Deptment of Radiotherapy & Oncology, 105860The Second Affiliated Hospital of Soochow University, Suzhou, China.,Department of Oncological Surgery, 74540The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Ye Tian
- Deptment of Radiotherapy & Oncology, 105860The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Gongsheng Jin
- Department of Oncological Surgery, 74540The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Zhen Cui
- Department of Oncological Surgery, 74540The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Wei Guo
- Department of Oncological Surgery, 74540The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Xiaojing Zhang
- Department of Oncological Surgery, 74540The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Xianfu Liu
- Department of Oncological Surgery, 74540The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
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Li M, Thorne RF, Shi R, Zhang XD, Li J, Li J, Zhang Q, Wu M, Liu L. DDIT3 Directs a Dual Mechanism to Balance Glycolysis and Oxidative Phosphorylation during Glutamine Deprivation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2003732. [PMID: 34105294 PMCID: PMC8188220 DOI: 10.1002/advs.202003732] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 01/29/2021] [Indexed: 05/26/2023]
Abstract
Extracellular glutamine represents an important energy source for many cancer cells and its metabolism is intimately involved in maintaining redox homeostasis. The heightened metabolic activity within tumor tissues can result in glutamine deficiency, necessitating metabolic reprogramming responses. Here, dual mechanisms involving the stress-responsive transcription factor DDIT3 (DNA damage induced transcript 3) that establishes an interrelationship between glycolysis and mitochondrial respiration are revealed. DDIT3 is induced during glutamine deprivation to promote glycolysis and adenosine triphosphate production via suppression of the negative glycolytic regulator TIGAR. In concert, a proportion of the DDIT3 pool translocates to the mitochondria and suppresses oxidative phosphorylation through LONP1-mediated down-regulation of COQ9 and COX4. This in turn dampens the sustained levels of reactive oxygen species that follow glutamine withdrawal. Together these mechanisms constitute an adaptive survival mechanism permitting tumor cells to survive metabolic stress induced by glutamine starvation.
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Affiliation(s)
- Mingyue Li
- Heifei National Laboratory for Physical Sciences at the Microscale of USTCCAS Centre for Excellence in Molecular Cell Sciencethe First Affiliated Hospital of University of Science and Technology of ChinaHefeiAnhui230027China
| | - Rick Francis Thorne
- Translational Research InstituteHenan Provincial People's HospitalSchool of Clinical MedicineHenan UniversityZhengzhouHenan450003China
| | - Ronghua Shi
- Heifei National Laboratory for Physical Sciences at the Microscale of USTCCAS Centre for Excellence in Molecular Cell Sciencethe First Affiliated Hospital of University of Science and Technology of ChinaHefeiAnhui230027China
| | - Xu Dong Zhang
- Translational Research InstituteHenan Provincial People's HospitalSchool of Clinical MedicineHenan UniversityZhengzhouHenan450003China
| | - Jingmin Li
- Translational Research InstituteHenan Provincial People's HospitalSchool of Clinical MedicineHenan UniversityZhengzhouHenan450003China
- Harbin Medical University Cancer HospitalHarbinHeilongjiang150081China
| | - Jingtong Li
- Harbin Medical University Cancer HospitalHarbinHeilongjiang150081China
| | - Qingyuan Zhang
- Harbin Medical University Cancer HospitalHarbinHeilongjiang150081China
| | - Mian Wu
- Heifei National Laboratory for Physical Sciences at the Microscale of USTCCAS Centre for Excellence in Molecular Cell Sciencethe First Affiliated Hospital of University of Science and Technology of ChinaHefeiAnhui230027China
- Translational Research InstituteHenan Provincial People's HospitalSchool of Clinical MedicineHenan UniversityZhengzhouHenan450003China
| | - Lianxin Liu
- Heifei National Laboratory for Physical Sciences at the Microscale of USTCCAS Centre for Excellence in Molecular Cell Sciencethe First Affiliated Hospital of University of Science and Technology of ChinaHefeiAnhui230027China
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Yu W, Yang X, Zhang Q, Sun L, Yuan S, Xin Y. Targeting GLS1 to cancer therapy through glutamine metabolism. Clin Transl Oncol 2021; 23:2253-2268. [PMID: 34023970 DOI: 10.1007/s12094-021-02645-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 05/12/2021] [Indexed: 12/22/2022]
Abstract
Glutamine metabolism is one of the hallmarks of cancers which is described as an essential role in serving as a major energy and building blocks supply to cell proliferation in cancer cells. Many malignant tumor cells always display glutamine addiction. The "kidney-type" glutaminase (GLS1) is a metabolism enzyme which plays a significant part in glutaminolysis. Interestingly, GLS1 is often overexpressed in highly proliferative cancer cells to fulfill enhanced glutamine demand. So far, GLS1 has been proved to be a significant target during the carcinogenesis process, and emerging evidence reveals that its inhibitors could provide a benefit strategy for cancer therapy. Herein, we summarize the prognostic value of GLS1 in multiple cancer type and its related regulatory factors which are associated with antitumor activity. Moreover, this review article highlights the remarkable reform of discovery and development for GLS1 inhibitors. On the basis of case studies, our perspectives for targeting GLS1 and development of GLS1 antagonist are discussed in the final part.
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Affiliation(s)
- Wei Yu
- China Pharmaceutical University, Nanjing, 21000, Jiangsu, China
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated With Jinan University, Jinan University, Zhuhai, 519000, Guangdong, China
| | - XiangYu Yang
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated With Jinan University, Jinan University, Zhuhai, 519000, Guangdong, China
| | - Qian Zhang
- China Pharmaceutical University, Nanjing, 21000, Jiangsu, China
| | - Li Sun
- China Pharmaceutical University, Nanjing, 21000, Jiangsu, China
| | - ShengTao Yuan
- China Pharmaceutical University, Nanjing, 21000, Jiangsu, China.
| | - YongJie Xin
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated With Jinan University, Jinan University, Zhuhai, 519000, Guangdong, China.
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40
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Bustos G, Ahumada-Castro U, Silva-Pavez E, Puebla A, Lovy A, Cesar Cardenas J. The ER-mitochondria Ca 2+ signaling in cancer progression: Fueling the monster. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 363:49-121. [PMID: 34392932 DOI: 10.1016/bs.ircmb.2021.03.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cancer is a leading cause of death worldwide. All major tumor suppressors and oncogenes are now recognized to have fundamental connections with metabolic pathways. A hallmark feature of cancer cells is a reprogramming of their metabolism even when nutrients are available. Increasing evidence indicates that most cancer cells rely on mitochondrial metabolism to sustain their energetic and biosynthetic demands. Mitochondria are functionally and physically coupled to the endoplasmic reticulum (ER), the major calcium (Ca2+) storage organelle in mammalian cells, through special domains known as mitochondria-ER contact sites (MERCS). In this domain, the release of Ca2+ from the ER is mainly regulated by inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), a family of Ca2+ release channels activated by the ligand IP3. IP3R mediated Ca2+ release is transferred to mitochondria through the mitochondrial Ca2+ uniporter (MCU). Once in the mitochondrial matrix, Ca2+ activates several proteins that stimulate mitochondrial performance. The role of IP3R and MCU in cancer, as well as the other proteins that enable the Ca2+ communication between these two organelles is just beginning to be understood. Here, we describe the function of the main players of the ER mitochondrial Ca2+ communication and discuss how this particular signal may contribute to the rise and development of cancer traits.
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Affiliation(s)
- Galdo Bustos
- Faculty of Sciences, Universidad Mayor, Center for Integrative Biology, Santiago, Chile; Geroscience Center for Brain Health and Metabolism, Santiago, Chile
| | - Ulises Ahumada-Castro
- Faculty of Sciences, Universidad Mayor, Center for Integrative Biology, Santiago, Chile; Geroscience Center for Brain Health and Metabolism, Santiago, Chile
| | - Eduardo Silva-Pavez
- Faculty of Sciences, Universidad Mayor, Center for Integrative Biology, Santiago, Chile; Geroscience Center for Brain Health and Metabolism, Santiago, Chile
| | - Andrea Puebla
- Faculty of Sciences, Universidad Mayor, Center for Integrative Biology, Santiago, Chile; Geroscience Center for Brain Health and Metabolism, Santiago, Chile
| | - Alenka Lovy
- Faculty of Sciences, Universidad Mayor, Center for Integrative Biology, Santiago, Chile; Geroscience Center for Brain Health and Metabolism, Santiago, Chile; Department of Neuroscience, Center for Neuroscience Research, Tufts School of Medicine, Boston, MA, United States.
| | - J Cesar Cardenas
- Faculty of Sciences, Universidad Mayor, Center for Integrative Biology, Santiago, Chile; Geroscience Center for Brain Health and Metabolism, Santiago, Chile; Buck Institute for Research on Aging, Novato, CA, United States; Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, United States.
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41
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Inhibition of InsP3R with Xestospongin B Reduces Mitochondrial Respiration and Induces Selective Cell Death in T Cell Acute Lymphoblastic Leukemia Cells. Int J Mol Sci 2021; 22:ijms22020651. [PMID: 33440859 PMCID: PMC7827595 DOI: 10.3390/ijms22020651] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 12/31/2020] [Accepted: 01/05/2021] [Indexed: 02/07/2023] Open
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy whose chemoresistance and relapse persist as a problem despite significant advances in its chemotherapeutic treatments. Mitochondrial metabolism has emerged as an interesting therapeutic target given its essential role in maintaining bioenergetic and metabolic homeostasis. T-ALL cells are characterized by high levels of mitochondrial respiration, making them suitable for this type of intervention. Mitochondrial function is sustained by a constitutive transfer of calcium from the endoplasmic reticulum to mitochondria through the inositol 1,4,5-trisphosphate receptor (InsP3R), making T-ALL cells vulnerable to its inhibition. Here, we determine the bioenergetic profile of the T-ALL cell lines CCRF-CEM and Jurkat and evaluate their sensitivity to InsP3R inhibition with the specific inhibitor, Xestospongin B (XeB). Our results show that T-ALL cell lines exhibit higher mitochondrial respiration than non-malignant cells, which is blunted by the inhibition of the InsP3R. Prolonged treatment with XeB causes T-ALL cell death without affecting the normal counterpart. Moreover, the combination of XeB and glucocorticoids significantly enhanced cell death in the CCRF-CEM cells. The inhibition of InsP3R with XeB rises as a potential therapeutic alternative for the treatment of T-ALL.
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42
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Xu L, Chen J, Jia L, Chen X, Awaleh Moumin F, Cai J. SLC1A3 promotes gastric cancer progression via the PI3K/AKT signalling pathway. J Cell Mol Med 2020; 24:14392-14404. [PMID: 33145952 PMCID: PMC7753768 DOI: 10.1111/jcmm.16060] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 09/27/2020] [Accepted: 10/19/2020] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is a major cause of mortality worldwide. The glutamate/aspartate transporter SLC1A3 has been implicated in tumour metabolism and progression, but the roles of SLC1A3 in gastric cancer remain unclear. We used bioinformatics approaches to analyse the expression of SLC1A3 and its role in gastric cancer. The expression levels of SLC1A3 were examined using RT-qPCR and Western bolting. SLC1A3 overexpressing and knock-down cell lines were constructed, and the cell viability was evaluated. Glucose consumption, lactate excretion and ATP levels were determined. The roles of SLC1A3 in tumour growth were evaluated using a xenograft tumour growth model. SLC1A3 was found to be overexpressed in gastric cancer, and this overexpression was associated with poor prognosis. In vitro and in vivo assays showed that SLC1A3 affected glucose metabolism and promoted gastric cancer growth. GSEA analysis suggested that SLC1A3 was positively associated with the up-regulation of the PI3K/AKT pathway. SLC1A3 overexpression activated the PI3K/AKT pathway and up-regulated GLUT1, HK II and LDHA expression. The PI3K/AKT inhibitor LY294002 prevented SLC1A3-induced glucose metabolism and cell proliferation. Our findings indicate that SLC1A3 promotes gastric cancer progression via the PI3K/AKT signalling pathway. SLC1A3 is therefore a potential therapeutic target in gastric cancer.
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Affiliation(s)
- Liyi Xu
- Department of Gastroenterologythe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Jiamin Chen
- Department of Gastroenterologythe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Litao Jia
- Department of Gastroenterologythe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Xiao Chen
- Emergency Departmentthe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Faycal Awaleh Moumin
- Department of Gastroenterologythe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Jianting Cai
- Department of Gastroenterologythe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
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Borst P. The malate-aspartate shuttle (Borst cycle): How it started and developed into a major metabolic pathway. IUBMB Life 2020; 72:2241-2259. [PMID: 32916028 PMCID: PMC7693074 DOI: 10.1002/iub.2367] [Citation(s) in RCA: 134] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 12/20/2022]
Abstract
This article presents a personal and critical review of the history of the malate-aspartate shuttle (MAS), starting in 1962 and ending in 2020. The MAS was initially proposed as a route for the oxidation of cytosolic NADH by the mitochondria in Ehrlich ascites cell tumor lacking other routes, and to explain the need for a mitochondrial aspartate aminotransferase (glutamate oxaloacetate transaminase 2 [GOT2]). The MAS was soon adopted in the field as a major pathway for NADH oxidation in mammalian tissues, such as liver and heart, even though the energetics of the MAS remained a mystery. Only in the 1970s, LaNoue and coworkers discovered that the efflux of aspartate from mitochondria, an essential step in the MAS, is dependent on the proton-motive force generated by the respiratory chain: for every aspartate effluxed, mitochondria take up one glutamate and one proton. This makes the MAS in practice uni-directional toward oxidation of cytosolic NADH, and explains why the free NADH/NAD ratio is much higher in the mitochondria than in the cytosol. The MAS is still a very active field of research. Most recently, the focus has been on the role of the MAS in tumors, on cells with defects in mitochondria and on inborn errors in the MAS. The year 2019 saw the discovery of two new inborn errors in the MAS, deficiencies in malate dehydrogenase 1 and in aspartate transaminase 2 (GOT2). This illustrates the vitality of ongoing MAS research.
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Affiliation(s)
- Piet Borst
- Division of Cell BiologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
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44
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Shen YA, Hong J, Asaka R, Asaka S, Hsu FC, Suryo Rahmanto Y, Jung JG, Chen YW, Yen TT, Tomaszewski A, Zhang C, Attarwala N, DeMarzo AM, Davidson B, Chuang CM, Chen X, Gaillard S, Le A, Shih IM, Wang TL. Inhibition of the MYC-Regulated Glutaminase Metabolic Axis Is an Effective Synthetic Lethal Approach for Treating Chemoresistant Ovarian Cancers. Cancer Res 2020; 80:4514-4526. [PMID: 32859605 DOI: 10.1158/0008-5472.can-19-3971] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 06/21/2020] [Accepted: 08/25/2020] [Indexed: 12/17/2022]
Abstract
Amplification and overexpression of the MYC oncogene in tumor cells, including ovarian cancer cells, correlates with poor responses to chemotherapy. As MYC is not directly targetable, we have analyzed molecular pathways downstream of MYC to identify potential therapeutic targets. Here we report that ovarian cancer cells overexpressing glutaminase (GLS), a target of MYC and a key enzyme in glutaminolysis, are intrinsically resistant to platinum-based chemotherapy and are enriched with intracellular antioxidant glutathione. Deprivation of glutamine by glutamine-withdrawal, GLS knockdown, or exposure to the GLS inhibitor CB-839 resulted in robust induction of reactive oxygen species in high GLS-expressing but not in low GLS-expressing ovarian cancer cells. Treatment with CB-839 rendered GLShigh cells vulnerable to the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, and prolonged survival in tumor-bearing mice. These findings suggest consideration of applying a combined therapy of GLS inhibitor and PARP inhibitor to treat chemoresistant ovarian cancers, especially those with high GLS expression. SIGNIFICANCE: Targeting glutaminase disturbs redox homeostasis and nucleotide synthesis and causes replication stress in cancer cells, representing an exploitable vulnerability for the development of effective therapeutics. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4514/F1.large.jpg.
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Affiliation(s)
- Yao-An Shen
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jiaxin Hong
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ryoichi Asaka
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Shiho Asaka
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Fang-Chi Hsu
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan
| | - Yohan Suryo Rahmanto
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jin-Gyoung Jung
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Yu-Wei Chen
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ting-Tai Yen
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Alicja Tomaszewski
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Cissy Zhang
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nabeel Attarwala
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Angelo M DeMarzo
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ben Davidson
- Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Chi-Mu Chuang
- College of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan.,Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Xi Chen
- Bradley Department of Electrical and Computer Engineering, Virginia Tech, Arlington, Virginia
| | - Stephanie Gaillard
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Anne Le
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ie-Ming Shih
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. .,Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Tian-Li Wang
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. .,Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
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45
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Lane AN, Higashi RM, Fan TWM. Metabolic reprogramming in tumors: Contributions of the tumor microenvironment. Genes Dis 2020; 7:185-198. [PMID: 32215288 PMCID: PMC7083762 DOI: 10.1016/j.gendis.2019.10.007] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 10/06/2019] [Accepted: 10/16/2019] [Indexed: 12/22/2022] Open
Abstract
The genetic alterations associated with cell transformation are in large measure expressed in the metabolic phenotype as cancer cells proliferate and change their local environment, and prepare for metastasis. Qualitatively, the fundamental biochemistry of cancer cells is generally the same as in the untransformed cells, but the cancer cells produce a local environment, the TME, that is hostile to the stromal cells, and compete for nutrients. In order to proliferate, cells need sufficient nutrients, either those that cannot be made by the cells themselves, or must be made from simpler precursors. However, in solid tumors, the nutrient supply is often limiting given the potential for rapid proliferation, and the poor quality of the vasculature. Thus, cancer cells may employ a variety of strategies to obtain nutrients for survival, growth and metastasis. Although much has been learned using established cell lines in standard culture conditions, it is becoming clear from in vivo metabolic studies that this can also be misleading, and which nutrients are used for energy production versus building blocks for synthesis of macromolecules can vary greatly from tumor to tumor, and even within the same tumor. Here we review the operation of metabolic networks, and how recent understanding of nutrient supply in the TME and utilization are being revealed using stable isotope tracers in vivo as well as in vitro.
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Key Words
- 2OG, 2-oxoglutarate
- ACO1,2, aconitase 1,2
- CP-MAS, Cross polarization Magic Angle Spinning
- Cancer metabolism
- DMEM, Dulbeccos Modified Eagles Medium
- ECAR, extracellular acidification rate
- ECM, extracellular matrix
- EMP, Embden-Meyerhof Pathway
- IDH1,2, isocitrate dehydrogenase 1,2 (NADP+dependent)
- IF, interstitial fluid
- ME, malic enzyme
- Metabolic flux
- Nutrient supply
- RPMI, Roswell Park Memorial Institute
- SIRM, Stable Isotope Resolved Metabolomics
- Stable isotope resolved metabolomics
- TIL, tumor infiltrating lymphocyte
- TIM/TPI, triose phosphate isomerase
- TME, Tumor Micro Environment
- Tumor microenvironment
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Affiliation(s)
- Andrew N. Lane
- Center for Environmental and Systems Biochemistry, Markey Cancer Center, Department of Toxicology and Cancer Biology, University of Kentucky, USA
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46
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Fritsche-Guenther R, Gloaguen Y, Kirchner M, Mertins P, Tunn PU, Kirwan JA. Progression-Dependent Altered Metabolism in Osteosarcoma Resulting in Different Nutrient Source Dependencies. Cancers (Basel) 2020; 12:cancers12061371. [PMID: 32471029 PMCID: PMC7352851 DOI: 10.3390/cancers12061371] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/07/2020] [Accepted: 05/20/2020] [Indexed: 12/13/2022] Open
Abstract
Osteosarcoma (OS) is a primary malignant bone tumor and OS metastases are mostly found in the lung. The limited understanding of the biology of metastatic processes in OS limits the ability for effective treatment. Alterations to the metabolome and its transformation during metastasis aids the understanding of the mechanism and provides information on treatment and prognosis. The current study intended to identify metabolic alterations during OS progression by using a targeted gas chromatography mass spectrometry approach. Using a female OS cell line model, malignant and metastatic cells increased their energy metabolism compared to benign OS cells. The metastatic cell line showed a faster metabolic flux compared to the malignant cell line, leading to reduced metabolite pools. However, inhibiting both glycolysis and glutaminolysis resulted in a reduced proliferation. In contrast, malignant but non-metastatic OS cells showed a resistance to glycolytic inhibition but a strong dependency on glutamine as an energy source. Our in vivo metabolic approach hinted at a potential sex-dependent metabolic alteration in OS patients with lung metastases (LM), although this will require validation with larger sample sizes. In line with the in vitro results, we found that female LM patients showed a decreased central carbon metabolism compared to metastases from male patients.
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Affiliation(s)
- Raphaela Fritsche-Guenther
- Berlin Institute of Health Metabolomics Platform, Berlin Institute of Health (BIH), 13125 Berlin, Germany; (Y.G.); (J.A.K.)
- Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Association, 13125 Berlin, Germany; (M.K.); (P.M.)
- Correspondence:
| | - Yoann Gloaguen
- Berlin Institute of Health Metabolomics Platform, Berlin Institute of Health (BIH), 13125 Berlin, Germany; (Y.G.); (J.A.K.)
- Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Association, 13125 Berlin, Germany; (M.K.); (P.M.)
- Core Unit Bioinformatics, Berlin Institute of Health (BIH), 10178 Berlin, Germany
| | - Marieluise Kirchner
- Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Association, 13125 Berlin, Germany; (M.K.); (P.M.)
- Proteomics Platform Berlin Institute of Health (BIH) and Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Association, 13125 Berlin, Germany
| | - Philipp Mertins
- Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Association, 13125 Berlin, Germany; (M.K.); (P.M.)
- Proteomics Platform Berlin Institute of Health (BIH) and Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Association, 13125 Berlin, Germany
| | - Per-Ulf Tunn
- Department of Orthopedic Oncology, Helios Clinic Berlin-Buch, 13125 Berlin, Germany;
| | - Jennifer A. Kirwan
- Berlin Institute of Health Metabolomics Platform, Berlin Institute of Health (BIH), 13125 Berlin, Germany; (Y.G.); (J.A.K.)
- Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Association, 13125 Berlin, Germany; (M.K.); (P.M.)
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47
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Zhou Y, Zhang J, Wang K, Han W, Wang X, Gao M, Wang Z, Sun Y, Yan H, Zhang H, Xu X, Yang DH. Quercetin overcomes colon cancer cells resistance to chemotherapy by inhibiting solute carrier family 1, member 5 transporter. Eur J Pharmacol 2020; 881:173185. [PMID: 32422185 DOI: 10.1016/j.ejphar.2020.173185] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 04/26/2020] [Accepted: 05/09/2020] [Indexed: 01/08/2023]
Abstract
P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) remains a significant impediment to the success of cancer chemotherapy. The natural flavonoid Quercetin (Que) has been reported to be able to inhibit P-gp-mediated MDR in various cancer cells. However, the MDR reversal effect of Que on human colon cancer cells and its mechanism at the metabolic level requires further clarification. This study was designed to provide a better understanding of the MDR reversal effect of Que. Our present results showed that 33 μM of Que significantly improved the cytotoxicity of doxorubicin (Dox) to P-gp-overexpressed SW620/Ad300 cells by proliferation and apoptpsis assay. Further mechanism studies demonstrated that Que inhibited the ATP-driven transport activity of P-gp, which in turn increased the intracellular accumulation of Dox. The metabolomics studies based on UPLC-MS/MS analysis revealed that Que could reverse the MDR by significantly blocking D-glutamine and D-glutamate metabolism, and the underlying mechanism is that Que down-regulated the expression of the glutamine transporter solute sarrier family 1, member 5 (SLC1A5) in SW620/Ad300 cells. This is the first time to report that Que was a SLC1A5 inhibitor, which could be served as a template compound to potentially develop novel P-gp-mediated MDR reversal modulators in cancer chemotherapy.
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Affiliation(s)
- Yuanyuan Zhou
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China
| | - Junhong Zhang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China
| | - Kaili Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China
| | - Wenchao Han
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China
| | - Xinying Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China
| | - Ming Gao
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China
| | - Zihan Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China
| | - Yaxin Sun
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China
| | - Hao Yan
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China
| | - Hang Zhang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China.
| | - Xia Xu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China.
| | - Dong-Hua Yang
- College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, JamaicaNY, 11439, USA.
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48
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Tang C, Pan Q, Gao S, Sun A, Wen F, Tang G. Excitatory glutamate transporter EAAC1 as an important transporter of N-(2-[ 18F]fluoropropionyl)-L-glutamate in oncology PET imaging. Nucl Med Biol 2020; 84-85:55-62. [PMID: 32066035 DOI: 10.1016/j.nucmedbio.2020.02.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 01/24/2020] [Accepted: 02/09/2020] [Indexed: 02/06/2023]
Abstract
INTRODUCTION We have reported that N-(2-[18F]fluoropropionyl)-L-glutamate ([18F]FPGLU) was a potential amino acid tracer for tumor imaging with positron emission tomography (PET). In this study, the relationship between glutamate transporter excitatory amino acid carrier 1 (EAAC1) expression and [18F]FPGLU uptake in rat C6 glioma cell lines and human SPC-A-1 lung adenocarcinoma cell lines was investigated. METHODS The uptake of [18F]FPGLU was assessed in ATRA-treated and untreated C6 cell lines, and also in EAAC1 knock-down SPC-A-1(shRNA) cells and SPC-A-1(NT) control cells. PET imaging of [18F]FPGLU was performed on the SPC-A-1 and SPC-A-1 (shRNA)-bearing mice models. RESULTS The uptake of [18F]FPGLU in C6 cells increased significantly after induced by ATRA for 24, 48, and 72 h, which was closely related to expression of EAAC1 in C6 cells (R2 = 0.939). Compared with the SPC-A-1(NT) control cells, the uptake of [18F]FPGLU on EAAC1 knock-down SPC-A-1(shRNA) cells significantly decreased to 64.0%. Moreover, the uptake of [18F]FPGLU in EAAC1 knock-down SPC-A-1(shRNA) xenografts was significantly lower than that in SPC-A-1 xenografts, with tumor/muscle ratios of 3.01 vs. 1.67 at 60 min post-injection of [18F]FPGLU. CONCLUSION The transport mechanism of [18F]FPGLU in glioma C6 and lung adenocarcinoma SPC-A-1 cell lines mainly involves in glutamate transporter EAAC1. EAAC1 is an important transporter of N-(2-[18F]fluoropropionyl)-L-glutamate in oncologic PET imaging.
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Affiliation(s)
- Caihua Tang
- Department of Nuclear Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China; Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, Department of Nuclear Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Qiyong Pan
- Department of Nuclear Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Siyuan Gao
- Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, Department of Nuclear Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Aixia Sun
- Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, Department of Nuclear Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Fuhua Wen
- Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, Department of Nuclear Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Ganghua Tang
- Nanfang PET Center and Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, Department of Nuclear Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
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Dynamic PET/CT imaging of 18F-(2S, 4R)4-fluoroglutamine in healthy volunteers and oncological patients. Eur J Nucl Med Mol Imaging 2020; 47:2280-2292. [DOI: 10.1007/s00259-019-04543-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 09/20/2019] [Indexed: 02/07/2023]
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50
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Qin C, Yang G, Yang J, Ren B, Wang H, Chen G, Zhao F, You L, Wang W, Zhao Y. Metabolism of pancreatic cancer: paving the way to better anticancer strategies. Mol Cancer 2020; 19:50. [PMID: 32122374 PMCID: PMC7053123 DOI: 10.1186/s12943-020-01169-7] [Citation(s) in RCA: 243] [Impact Index Per Article: 48.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 02/24/2020] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is currently one of the most lethal diseases. In recent years, increasing evidence has shown that reprogrammed metabolism may play a critical role in the carcinogenesis, progression, treatment and prognosis of pancreatic cancer. Affected by internal or external factors, pancreatic cancer cells adopt extensively distinct metabolic processes to meet their demand for growth. Rewired glucose, amino acid and lipid metabolism and metabolic crosstalk within the tumor microenvironment contribute to unlimited pancreatic tumor progression. In addition, the metabolic reprogramming involved in pancreatic cancer resistance is also closely related to chemotherapy, radiotherapy and immunotherapy, and results in a poor prognosis. Reflective of the key role of metabolism, the number of preclinical and clinical trials about metabolism-targeted therapies for pancreatic cancer is increasing. The poor prognosis of pancreatic cancer patients might be largely improved after employing therapies that regulate metabolism. Thus, investigations of metabolism not only benefit the understanding of carcinogenesis and cancer progression but also provide new insights for treatments against pancreatic cancer.
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Affiliation(s)
- Cheng Qin
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China
| | - Jinshou Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China
| | - Bo Ren
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China
| | - Huanyu Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China
| | - Guangyu Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China
| | - Fangyu Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China. .,Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100023, PR China.
| | - Weibin Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China. .,Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100023, PR China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China. .,Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100023, PR China.
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