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Huang D, Cai H, Huang H. Serine metabolism in tumor progression and immunotherapy. Discov Oncol 2025; 16:628. [PMID: 40295433 PMCID: PMC12037972 DOI: 10.1007/s12672-025-02358-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 04/09/2025] [Indexed: 04/30/2025] Open
Abstract
Serine plays a vital role in various metabolic processes including the synthesis of proteins and other amino acids, which are essential for the cell proliferation and growth. Cancer cells either absorb exogenous serine or produce it through the serine synthesis pathway, enabling the generation of intracellular glycine and one-carbon units, which are crucial for nucleotide biosynthesis. This metabolic process, referred to as serine-glycine-one-carbon (SGOC) metabolism, is essential for tumorigenesis and exhibits considerable complexity and clinical significance. Enzymes involved in the SGOC pathway are linked to tumor growth, metastasis, and resistance to therapies. The SGOC pathway is a vital metabolic network that facilitates cell survival and proliferation, especially in aggressive cancers. Understanding how this network is regulated is crucial for tackling tumor heterogeneity and recurrence. This review emphasizes recent advancements in understanding the roles and effects of the SGOC metabolic pathway in the context of cancer progression. Additionally, it outlines the complex influences of the SGOC metabolic pathway on the tumor microenvironment (TME), offering potential strategies to enhance cancer immunotherapy.
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Affiliation(s)
- Dong Huang
- Oncology Hematology Department, Fengdu General Hospital, Fengdu County, Chongqing, 408200, China
| | - Hui Cai
- Oncology Hematology Department, Fengdu General Hospital, Fengdu County, Chongqing, 408200, China
| | - HaiYu Huang
- Oncology Hematology Department, Fengdu General Hospital, Fengdu County, Chongqing, 408200, China.
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2
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Onyiba CI, Kumar NK, Scarlett CJ, Weidenhofer J. Cell Progression and Survival Functions of Enzymes Secreted in Extracellular Vesicles Associated with Breast and Prostate Cancers. Cells 2025; 14:468. [PMID: 40214422 PMCID: PMC11988166 DOI: 10.3390/cells14070468] [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: 02/25/2025] [Revised: 03/16/2025] [Accepted: 03/18/2025] [Indexed: 04/14/2025] Open
Abstract
Extracellular vesicles (EVs) are membrane-bound cargoes secreted by normal and pathological cells. Through their protein, nucleic acid, and lipid cargoes, EVs mediate several cellular processes, such as cell-cell communication, cell development, immune response, and tissue repair. Most importantly, through their enzyme cargo, EVs mediate pathophysiological processes, including the pathogenesis of cancer. In this review, we enumerate several enzymes secreted in EVs (EV enzyme cargo) from cells and patient clinical samples of breast and prostate cancers and detail their contributions to the progression and survival of both cancers. Findings in this review reveal that the EV enzyme cargo could exert cell progression functions via adhesion, proliferation, migration, invasion, and metastasis. The EV enzyme cargo might also influence cell survival functions of chemoresistance, radioresistance, angiogenesis, cell death inhibition, cell colony formation, and immune evasion. While the current literature provides evidence of the possible contributions of the EV enzyme cargo to the progression and survival mechanisms of breast and prostate cancers, future studies are required to validate that these effects are modified by EVs and provide insights into the clinical applications of the EV enzyme cargo in breast and prostate cancer.
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Affiliation(s)
- Cosmos Ifeanyi Onyiba
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Ourimbah, NSW 2258, Australia
- Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Niwasini Krishna Kumar
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Ourimbah, NSW 2258, Australia
- School of Health Sciences, International Medical University, Kuala Lumpur 57000, Malaysia
| | - Christopher J. Scarlett
- Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
- School of Environmental and Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Ourimbah, NSW 2258, Australia
| | - Judith Weidenhofer
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Ourimbah, NSW 2258, Australia
- Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
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3
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El-Far A, Liu X, Xiao T, Du J, Du X, Wei C, Cheng J, Zou H, Fu J. TQFL19, a Novel Derivative of Thymoquinone (TQ), Plays an Essential Role by Inhibiting Cell Growth, Metastasis, and Invasion in Triple-Negative Breast Cancer. Molecules 2025; 30:773. [PMID: 40005083 PMCID: PMC11858164 DOI: 10.3390/molecules30040773] [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: 12/04/2024] [Revised: 01/26/2025] [Accepted: 01/30/2025] [Indexed: 02/27/2025] Open
Abstract
Breast cancer (BC) is a significant public health concern globally. Triple-negative breast cancer (TNBC) is considered the most challenging type, as it is defined by an absence of estrogen and progesterone receptor expression, along with a lack of HER2 overexpression. In the current study, we developed a novel thymoquinone (TQ), TQFL19, to control TNBC progression. Purpose: The current study aimed to investigate the anticancer potential of a newly synthesized TQFL19 against TNBC. Study design: To achieve our research goals, we meticulously developed both in vitro and in vivo studies focused on TNBC cell growth, metastasis, and invasion. Results: Characterization and ADMET properties prediction of TQFL19 were first performed before treating TNBC cells. TQFL19 exhibited more potent cytotoxicity than TQ against 4T1, BT-549, and MDA-MB-231 cells and induced apoptosis of 4T1 and MDA-MB-231, besides cell cycle arrest of MDA-MB-231. In vivo mice allograft of 4T1 revealed the ability of TQFL19 to hinder the growth, migration, and metastasis of TNBC cells. Conclusions: The results suggest that TQFL19 potentially inhibited TNBC growth, metastasis, and invasion. The results conclude that TQFL19 could be a viable candidate for TNBC therapy.
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Affiliation(s)
- Ali El-Far
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou 646000, China; (A.E.-F.); (X.L.); (T.X.); (C.W.); (J.C.)
| | - Xiaoyan Liu
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou 646000, China; (A.E.-F.); (X.L.); (T.X.); (C.W.); (J.C.)
| | - Ting Xiao
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou 646000, China; (A.E.-F.); (X.L.); (T.X.); (C.W.); (J.C.)
| | - Jun Du
- Department of Chemistry, Southwest Medical University, Luzhou 646000, China;
| | - Xinwei Du
- School of Pharmacy, Southwest Medical University, Luzhou 646000, China;
| | - Chunli Wei
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou 646000, China; (A.E.-F.); (X.L.); (T.X.); (C.W.); (J.C.)
| | - Jingliang Cheng
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou 646000, China; (A.E.-F.); (X.L.); (T.X.); (C.W.); (J.C.)
| | - Hui Zou
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou 646000, China; (A.E.-F.); (X.L.); (T.X.); (C.W.); (J.C.)
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha 410013, China
| | - Junjiang Fu
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou 646000, China; (A.E.-F.); (X.L.); (T.X.); (C.W.); (J.C.)
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4
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Biyik-Sit R, Waigel S, Andreeva K, Rouchka E, Clem BF. Bioinformatics analysis of PSAT1 loss identifies downstream pathways regulated in EGFR mutant NSCLC and a selective gene signature for predicting the risk of relapse. Oncol Lett 2025; 29:9. [PMID: 39512505 PMCID: PMC11542166 DOI: 10.3892/ol.2024.14755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 09/25/2024] [Indexed: 11/15/2024] Open
Abstract
The majority of malignant tumors exhibit an altered metabolic phenotype that ultimately provides the required energy and molecular precursors necessary for unregulated cell division. Within this, phosphoserine aminotransferase 1 (PSAT1) is involved in de novo serine biosynthesis and its activity promotes various biochemical processes, including one-carbon metabolism. It also directly generates α-ketoglutarate (α-KG), a Kreb cycle intermediate and epigenetic-regulating metabolite. Prior studies examining PSAT1 depletion have identified individual affected downstream pathways, such as GSK3β and E2F, in several cancer types, including non-small-cell lung cancer (NSCLC). However, global gene expression examination in response to PSAT1 loss, particularly in EGFR mutant NSCLC, has not been unexplored. Transcriptional profiling of EGFR mutant NSCLC cells with or without stable knock-down of PSAT1 identified differentially expressed genes (DEGs) enriched in several metabolic pathways required for cell division, including amino acid and nucleotide biosynthesis. Supplementation studies involving non-essential amino acids, nucleosides and α-KG partially restored defects in anchorage-independent growth due to the knockdown of PSAT1. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis identified potential impacts on actin cytoskeleton arrangement and β-catenin activity, which were rescued by PSAT1 re-expression. Finally, a comparative analysis of PSAT1 DEGs against transcripts enriched in patient EGFR mutant lung tumors identified a gene signature that is associated with overall and relapse-free survival (RFS) and was able to distinguish low or high-risk populations for RFS in early-stage EGFR mutant NSCLC. Overall, investigating genes altered by PSAT1 loss confirmed known PSAT1-regulated cellular pathways, identified a previously unknown role in the mediation of cytoskeleton arrangement in EGFR mutant NSCLC cells and allowed for the characterization of a gene signature with putative predictive potential for RFS in early-stage disease.
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Affiliation(s)
- Rumeysa Biyik-Sit
- Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40202, USA
- Brown Cancer Center, Louisville, KY 40202, USA
| | - Sabine Waigel
- Brown Cancer Center, Louisville, KY 40202, USA
- Kentucky IDeA Network of Biomedical Research Excellence Bioinformatics Core, University of Louisville, Louisville, KY 40202, USA
| | - Kalina Andreeva
- Kentucky IDeA Network of Biomedical Research Excellence Bioinformatics Core, University of Louisville, Louisville, KY 40202, USA
- Department of Neuroscience Training, University of Louisville, Louisville, KY 40202, USA
| | - Eric Rouchka
- Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40202, USA
- Kentucky IDeA Network of Biomedical Research Excellence Bioinformatics Core, University of Louisville, Louisville, KY 40202, USA
| | - Brian F Clem
- Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40202, USA
- Brown Cancer Center, Louisville, KY 40202, USA
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5
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Bel’skaya LV, Dyachenko EI. Oxidative Stress in Breast Cancer: A Biochemical Map of Reactive Oxygen Species Production. Curr Issues Mol Biol 2024; 46:4646-4687. [PMID: 38785550 PMCID: PMC11120394 DOI: 10.3390/cimb46050282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/08/2024] [Accepted: 05/11/2024] [Indexed: 05/25/2024] Open
Abstract
This review systematizes information about the metabolic features of breast cancer directly related to oxidative stress. It has been shown those redox changes occur at all levels and affect many regulatory systems in the human body. The features of the biochemical processes occurring in breast cancer are described, ranging from nonspecific, at first glance, and strictly biochemical to hormone-induced reactions, genetic and epigenetic regulation, which allows for a broader and deeper understanding of the principles of oncogenesis, as well as maintaining the viability of cancer cells in the mammary gland. Specific pathways of the activation of oxidative stress have been studied as a response to the overproduction of stress hormones and estrogens, and specific ways to reduce its negative impact have been described. The diversity of participants that trigger redox reactions from different sides is considered more fully: glycolytic activity in breast cancer, and the nature of consumption of amino acids and metals. The role of metals in oxidative stress is discussed in detail. They can act as both co-factors and direct participants in oxidative stress, since they are either a trigger mechanism for lipid peroxidation or capable of activating signaling pathways that affect tumorigenesis. Special attention has been paid to the genetic and epigenetic regulation of breast tumors. A complex cascade of mechanisms of epigenetic regulation is explained, which made it possible to reconsider the existing opinion about the triggers and pathways for launching the oncological process, the survival of cancer cells and their ability to localize.
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Affiliation(s)
- Lyudmila V. Bel’skaya
- Biochemistry Research Laboratory, Omsk State Pedagogical University, 644099 Omsk, Russia;
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Sunassee ED, Deutsch RJ, D’Agostino VW, Castellano-Escuder P, Siebeneck EA, Ilkayeva O, Crouch BT, Madonna MC, Everitt J, Alvarez JV, Palmer GM, Hirschey MD, Ramanujam N. Optical imaging reveals chemotherapy-induced metabolic reprogramming of residual disease and recurrence. SCIENCE ADVANCES 2024; 10:eadj7540. [PMID: 38579004 PMCID: PMC10997195 DOI: 10.1126/sciadv.adj7540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 03/04/2024] [Indexed: 04/07/2024]
Abstract
Fewer than 20% of triple-negative breast cancer patients experience long-term responses to mainstay chemotherapy. Resistant tumor subpopulations use alternative metabolic pathways to escape therapy, survive, and eventually recur. Here, we show in vivo, longitudinal metabolic reprogramming in residual disease and recurrence of triple-negative breast cancer xenografts with varying sensitivities to the chemotherapeutic drug paclitaxel. Optical imaging coupled with metabolomics reported an increase in non-glucose-driven mitochondrial metabolism and an increase in intratumoral metabolic heterogeneity during regression and residual disease in resistant MDA-MB-231 tumors. Conversely, sensitive HCC-1806 tumors were primarily reliant on glucose uptake and minimal changes in metabolism or heterogeneity were observed over the tumors' therapeutic life cycles. Further, day-matched resistant HCC-1806 tumors revealed a higher reliance on mitochondrial metabolism and elevated metabolic heterogeneity compared to sensitive HCC-1806 tumors. Together, metabolic flexibility, increased reliance on mitochondrial metabolism, and increased metabolic heterogeneity are defining characteristics of persistent residual disease, features that will inform the appropriate type and timing of therapies.
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Affiliation(s)
| | - Riley J. Deutsch
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | | | - Pol Castellano-Escuder
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Durham, NC, USA
- Department of Pharmacology and Cancer Biology, School of Medicine, Duke University, Durham, NC, USA
- Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC, USA
| | | | - Olga Ilkayeva
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Durham, NC, USA
- Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC, USA
| | - Brian T. Crouch
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Megan C. Madonna
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Jeffrey Everitt
- Department of Pathology, School of Medicine, Duke University, Durham, NC, USA
| | - James V. Alvarez
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | | | - Matthew D. Hirschey
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Durham, NC, USA
- Department of Pharmacology and Cancer Biology, School of Medicine, Duke University, Durham, NC, USA
- Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC, USA
| | - Nirmala Ramanujam
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
- Department of Radiation Oncology, Duke University, Durham, NC, USA
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7
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Hsieh CH, Huang CT, Cheng YS, Hsu CH, Hsu WM, Chung YH, Liu YL, Yang TS, Chien CY, Lee YH, Huang HC, Juan HF. Homoharringtonine as a PHGDH inhibitor: Unraveling metabolic dependencies and developing a potent therapeutic strategy for high-risk neuroblastoma. Biomed Pharmacother 2023; 166:115429. [PMID: 37673018 DOI: 10.1016/j.biopha.2023.115429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/22/2023] [Accepted: 08/30/2023] [Indexed: 09/08/2023] Open
Abstract
Neuroblastoma, a childhood cancer affecting the sympathetic nervous system, continues to challenge the development of potent treatments due to the limited availability of druggable targets for this aggressive illness. Recent investigations have uncovered that phosphoglycerate dehydrogenase (PHGDH), an essential enzyme for de novo serine synthesis, serves as a non-oncogene dependency in high-risk neuroblastoma. In this study, we show that homoharringtonine (HHT) acts as a PHGDH inhibitor, inducing intricate alterations in cellular metabolism, and thus providing an efficient treatment for neuroblastoma. We have experimentally verified the reliance of neuroblastoma on PHGDH and employed molecular docking, thermodynamic evaluations, and X-ray crystallography techniques to determine the bond interactions between HHT and PHGDH. Administering HHT to treat neuroblastoma resulted in effective cell elimination in vitro and tumor reduction in vivo. Metabolite and functional assessments additionally disclosed that HHT treatment suppressed de novo serine synthesis, initiating intricate metabolic reconfiguration and oxidative stress in neuroblastoma. Collectively, these discoveries highlight the potential of targeting PHGDH using HHT as a potent approach for managing high-risk neuroblastoma.
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Affiliation(s)
- Chiao-Hui Hsieh
- Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC; Center for Computational and Systems Biology, National Taiwan University, Taipei, Taiwan, ROC
| | - Chen-Tsung Huang
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan, ROC
| | - Yi-Sheng Cheng
- Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC; Institute of Plant Biology, National Taiwan University, Taipei, Taiwan, ROC; Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan, ROC
| | - Chun-Hua Hsu
- Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan, ROC; Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan, ROC
| | - Wen-Ming Hsu
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, ROC
| | - Yun-Hsien Chung
- Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC
| | - Yen-Lin Liu
- Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC
| | - Tsai-Shan Yang
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, ROC
| | - Chia-Yu Chien
- Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan, ROC
| | - Yu-Hsuan Lee
- Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC
| | - Hsuan-Cheng Huang
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC.
| | - Hsueh-Fen Juan
- Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC; Center for Computational and Systems Biology, National Taiwan University, Taipei, Taiwan, ROC; Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan, ROC; Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan, ROC; Center for Advanced Computing and Imaging in Biomedicine, Taipei, Taiwan, ROC.
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8
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Kansara S, Singh A, Badal AK, Rani R, Baligar P, Garg M, Pandey AK. The emerging regulatory roles of non-coding RNAs associated with glucose metabolism in breast cancer. Semin Cancer Biol 2023; 95:1-12. [PMID: 37364663 DOI: 10.1016/j.semcancer.2023.06.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 04/20/2023] [Accepted: 06/20/2023] [Indexed: 06/28/2023]
Abstract
Altered energy metabolism is one of the hallmarks of tumorigenesis and essential for fulfilling the high demand for metabolic energy in a tumor through accelerating glycolysis and reprogramming the glycolysis metabolism through the Warburg effect. The dysregulated glucose metabolic pathways are coordinated not only by proteins coding genes but also by non-coding RNAs (ncRNAs) during the initiation and cancer progression. The ncRNAs are responsible for regulating numerous cellular processes under developmental and pathological conditions. Recent studies have shown that various ncRNAs such as microRNAs, circular RNAs, and long noncoding RNAs are extensively involved in rewriting glucose metabolism in human cancers. In this review, we demonstrated the role of ncRNAs in the progression of breast cancer with a focus on outlining the aberrant expression of glucose metabolic pathways. Moreover, we have discussed the existing and probable future applications of ncRNAs to regulate energy pathways along with their importance in the prognosis, diagnosis, and future therapeutics for human breast carcinoma.
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Affiliation(s)
- Samarth Kansara
- Amity Institute of Biotechnology, Amity University Haryana, Panchgaon, Manesar, Haryana 122413, India
| | - Agrata Singh
- Amity Institute of Biotechnology, Amity University Haryana, Panchgaon, Manesar, Haryana 122413, India
| | - Abhishesh Kumar Badal
- Amity Institute of Biotechnology, Amity University Haryana, Panchgaon, Manesar, Haryana 122413, India
| | - Reshma Rani
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, 201313, India
| | - Prakash Baligar
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Sector-125, Noida 201313, India
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Sector-125, Noida 201313, India
| | - Amit Kumar Pandey
- Amity Institute of Biotechnology, Amity University Haryana, Panchgaon, Manesar, Haryana 122413, India; National Institute of Pharmaceutical Education and Research, Ahmedabad, Palaj, Gandhinagar 382355, Gujarat, India.
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9
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Bel’skaya LV, Gundyrev IA, Solomatin DV. The Role of Amino Acids in the Diagnosis, Risk Assessment, and Treatment of Breast Cancer: A Review. Curr Issues Mol Biol 2023; 45:7513-7537. [PMID: 37754258 PMCID: PMC10527988 DOI: 10.3390/cimb45090474] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/05/2023] [Accepted: 09/12/2023] [Indexed: 09/28/2023] Open
Abstract
This review summarizes the role of amino acids in the diagnosis, risk assessment, imaging, and treatment of breast cancer. It was shown that the content of individual amino acids changes in breast cancer by an average of 10-15% compared with healthy controls. For some amino acids (Thr, Arg, Met, and Ser), an increase in concentration is more often observed in breast cancer, and for others, a decrease is observed (Asp, Pro, Trp, and His). The accuracy of diagnostics using individual amino acids is low and increases when a number of amino acids are combined with each other or with other metabolites. Gln/Glu, Asp, Arg, Leu/Ile, Lys, and Orn have the greatest significance in assessing the risk of breast cancer. The variability in the amino acid composition of biological fluids was shown to depend on the breast cancer phenotype, as well as the age, race, and menopausal status of patients. In general, the analysis of changes in the amino acid metabolism in breast cancer is a promising strategy not only for diagnosis, but also for developing new therapeutic agents, monitoring the treatment process, correcting complications after treatment, and evaluating survival rates.
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Affiliation(s)
- Lyudmila V. Bel’skaya
- Biochemistry Research Laboratory, Omsk State Pedagogical University, 644099 Omsk, Russia;
| | - Ivan A. Gundyrev
- Biochemistry Research Laboratory, Omsk State Pedagogical University, 644099 Omsk, Russia;
| | - Denis V. Solomatin
- Department of Mathematics and Mathematics Teaching Methods, Omsk State Pedagogical University, 644043 Omsk, Russia;
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Murali R, Balasubramaniam V, Srinivas S, Sundaram S, Venkatraman G, Warrier S, Dharmarajan A, Gandhirajan RK. Deregulated Metabolic Pathways in Ovarian Cancer: Cause and Consequence. Metabolites 2023; 13:metabo13040560. [PMID: 37110218 PMCID: PMC10141515 DOI: 10.3390/metabo13040560] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/06/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Ovarian cancers are tumors that originate from the different cells of the ovary and account for almost 4% of all the cancers in women globally. More than 30 types of tumors have been identified based on the cellular origins. Epithelial ovarian cancer (EOC) is the most common and lethal type of ovarian cancer which can be further divided into high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous carcinoma. Ovarian carcinogenesis has been long attributed to endometriosis which is a chronic inflammation of the reproductive tract leading to progressive accumulation of mutations. Due to the advent of multi-omics datasets, the consequences of somatic mutations and their role in altered tumor metabolism has been well elucidated. Several oncogenes and tumor suppressor genes have been implicated in the progression of ovarian cancer. In this review, we highlight the genetic alterations undergone by the key oncogenes and tumor suppressor genes responsible for the development of ovarian cancer. We also summarize the role of these oncogenes and tumor suppressor genes and their association with a deregulated network of fatty acid, glycolysis, tricarboxylic acid and amino acid metabolism in ovarian cancers. Identification of genomic and metabolic circuits will be useful in clinical stratification of patients with complex etiologies and in identifying drug targets for personalized therapies against cancer.
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Affiliation(s)
- Roopak Murali
- Department of Human Genetics, Faculty of Biomedical Sciences Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai 600116, India
| | - Vaishnavi Balasubramaniam
- Department of Human Genetics, Faculty of Biomedical Sciences Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai 600116, India
| | - Satish Srinivas
- Department of Radiation Oncology, Sri Ramachandra Medical College & Research Institute, Sri Ramachandra Institute of Higher Education & Research (Deemed to be University), Porur, Chennai 600116, India
| | - Sandhya Sundaram
- Department of Pathology, Sri Ramachandra Medical College & Research Institute, Sri Ramachandra Institute of Higher Education & Research (Deemed to be University), Porur, Chennai 600116, India
| | - Ganesh Venkatraman
- Department of Human Genetics, Faculty of Biomedical Sciences Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai 600116, India
| | - Sudha Warrier
- Division of Cancer Stem Cells and Cardiovascular Regeneration, School of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560065, India
- Cuor Stem Cellutions Pvt Ltd., Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560065, India
| | - Arun Dharmarajan
- Department of Biomedical Sciences, Faculty of Biomedical Sciences Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai 600116, India
- Stem Cell and Cancer Biology Laboratory, Curtin University, Perth, WA 6102, Australia
- School of Pharmacy and Biomedical Sciences, Curtin University, Perth, WA 6102, Australia
- Curtin Health and Innovation Research Institute, Curtin University, Perth, WA 6102, Australia
| | - Rajesh Kumar Gandhirajan
- Department of Human Genetics, Faculty of Biomedical Sciences Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai 600116, India
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11
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Gökmen-Polar Y, Gu Y, Polar A, Gu X, Badve SS. The Role of ESRP1 in the Regulation of PHGDH in Estrogen Receptor-Positive Breast Cancer. J Transl Med 2023; 103:100002. [PMID: 36925195 DOI: 10.1016/j.labinv.2022.100002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/21/2022] [Accepted: 09/20/2022] [Indexed: 01/11/2023] Open
Abstract
Resistance to hormone therapy leads to a recurrence of estrogen receptor-positive breast cancer. We have demonstrated that the epithelial splicing regulatory protein 1 (ESRP1) significantly affects cell/tumor growth and metabolism and is associated with a poor prognosis in this breast cancer subtype. In this study, we aimed to investigate the ESRP1 protein-messenger RNA (mRNA) interaction in hormone therapy-resistant breast cancer. RNA-binding protein immunoprecipitation (RIP) followed by Clariom D (Applied Biosystems/Thermo Fisher Scientific) transcriptomics microarray (RIP-Chip) was performed to identify mRNA-binding partners of ESRP1. The integration of RIP-Chip and immunoprecipitation-mass spectrometry analyses identified phosphoglycerate dehydrogenase (PHGDH), a key metabolic enzyme, as a binding partner of ESRP1 in hormone-resistant breast cancer. Bioinformatic analysis showed ESRP1 binding to the 5' untranslated region of PHGDH. RNA electrophoresis mobility shift assay and RIP-quantitative reverse transcription-polymerase chain reaction further validated the ESRP1-PHGDH binding. In addition, knockdown of ESRP1 decreased PHGDH mRNA stability significantly, suggesting the posttranscriptional regulation of PHGDH by ESRP1. The presence or absence of ESRP1 levels significantly affected the stability in tamoxifen-resistant LCC2 and fulvestrant-resistant LCC9 cells. PHGDH knockdown in tamoxifen-resistant cells further reduced the oxygen consumption rate (ranging from P = .005 and P = .02), mimicking the effects of ESRP1 knockdown. Glycolytic parameters were also altered (ranging P = .001 and P = .005). ESRP1 levels did not affect the stability of PHGDH in T-47D cells, although knockdown of PHGDH affected the growth of these cells. In conclusion, to our knowledge, this study, for the first time, reports that ESRP1 binds to the 5' untranslated region of PHGDH, increasing its mRNA stability in hormone therapy-resistant estrogen receptor-positive breast cancer. These findings provide evidence for a novel mechanism of action of RNA-binding proteins such as ESRP1. These new insights could assist in developing novel strategies for the treatment of hormone therapy-resistant breast cancer.
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Affiliation(s)
- Yesim Gökmen-Polar
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia; Emory University Winship Cancer Institute, Atlanta, Georgia.
| | - Yuan Gu
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Alper Polar
- Department of Chemistry, University of Florida, Gainesville, Florida
| | - Xiaoping Gu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Sunil S Badve
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia; Emory University Winship Cancer Institute, Atlanta, Georgia
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12
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The Relationship between Histological Composition and Metabolic Profile in Breast Tumors and Peritumoral Tissue Determined with 1H HR-MAS NMR Spectroscopy. Cancers (Basel) 2023; 15:cancers15041283. [PMID: 36831625 PMCID: PMC9954108 DOI: 10.3390/cancers15041283] [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: 01/15/2023] [Revised: 02/13/2023] [Accepted: 02/14/2023] [Indexed: 02/22/2023] Open
Abstract
Breast tumors constitute the complex entities composed of cancer cells and stromal components. The compositional heterogeneity should be taken into account in bulk tissue metabolomics studies. The aim of this work was to find the relation between the histological content and 1H HR-MAS (high-resolution magic angle spinning nuclear magnetic resonance) metabolic profiles of the tissue samples excised from the breast tumors and the peritumoral areas in 39 patients diagnosed with invasive breast carcinoma. The total number of the histologically verified specimens was 140. The classification accuracy of the OPLS-DA (Orthogonal Partial Least Squares Discriminant Analysis) model differentiating the cancerous from non-involved samples was 87% (sensitivity of 72.2%, specificity of 92.3%). The metabolic contents of the epithelial and stromal compartments were determined from a linear regression analysis of the levels of the evaluated compounds against the cancer cell fraction in 39 samples composed mainly of cancer cells and intratumoral fibrosis. The correlation coefficients between the levels of several metabolites and a tumor purity were found to be dependent on the tumor grade (I vs II/III). The comparison of the levels of the metabolites in the intratumoral fibrosis (obtained from the extrapolation of the regression lines to 0% cancer content) to those levels in the fibrous connective tissue beyond the tumors revealed a profound metabolic reprogramming in the former tissue. The joint analysis of the metabolic profiles of the stromal and epithelial compartments in the breast tumors contributes to the increased understanding of breast cancer biology.
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13
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Anti-colon cancer effects of Spirulina polysaccharide and its mechanism based on 3D models. Int J Biol Macromol 2023; 228:559-569. [PMID: 36581031 DOI: 10.1016/j.ijbiomac.2022.12.244] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 11/03/2022] [Accepted: 12/21/2022] [Indexed: 12/27/2022]
Abstract
Spirulina polysaccharides (PSP) possess significant biological properties. However, it is still a lack of investigation on the anti-colorectal cancer effect and mechanism. In this study, PSP showed significant effects on LoVo cell spheroids with an IC50 value of 0.1943 mg/mL. The analysis of transcriptomics and metabolomics indicated the impact of PSP on LoVo spheroid cells through involvement in the two pathways of "glycine, serine, and threonine metabolism" and "ABC transporters". And, the q-PCR data further verified the pointed mechanism of PSP on colon cancer (CC) by regulating the expression levels of relevant genes in the synthesis pathways of serine and glycine in tumor cells. Furthermore, the anti-colon cancer effects of PSP were verified via other human colon cancer cell lines HCT116 and HT29 spheroids (IC50 = 0.0646 mg/mL and 0.2213 mg/mL, respectively), and three patient-derived organoids (PDOs) with IC50 values ranging from 3.807 to 7.788 mg/mL. In addition, this study found that a mild concentration of PSP cannot enhance the anti-tumor effect of 5-Fu. And a significant inhibition was found of PSP in 5-Fu resistance organoids. These results illustrated that PSP could be a treatment or supplement for 5-Fu resistant colorectal cancer (CRC).
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14
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Zheng X, Ma H, Wang J, Huang M, Fu D, Qin L, Yin Q. Energy metabolism pathways in breast cancer progression: The reprogramming, crosstalk, and potential therapeutic targets. Transl Oncol 2022; 26:101534. [PMID: 36113343 PMCID: PMC9482139 DOI: 10.1016/j.tranon.2022.101534] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 08/14/2022] [Accepted: 09/04/2022] [Indexed: 11/19/2022] Open
Abstract
Breast cancer (BC) is a malignant tumor that seriously endangers health in women. BC, like other cancers, is accompanied by metabolic reprogramming. Among energy metabolism-related pathways, BC exhibits enhanced glycolysis, tricarboxylic acid (TCA) cycle, pentose phosphate pathway (PPP), glutamate metabolism, and fatty acid metabolism activities. These pathways facilitate the proliferation, growth and migration of BC cells. The progression of BC is closely related to the alterations in the activity or expression level of several metabolic enzymes, which are regulated by the intrinsic factors such as the key signaling and transcription factors. The metabolic reprogramming in the progression of BC is attributed to the aberrant expression of the signaling and transcription factors associated with the energy metabolism pathways. Understanding the metabolic mechanisms underlying the development of BC will provide a druggable potential for BC treatment and drug discovery.
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Affiliation(s)
- Xuewei Zheng
- School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, China
| | - Haodi Ma
- School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, China
| | - Jingjing Wang
- School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, China
| | - Mengjiao Huang
- School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, China
| | - Dongliao Fu
- School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, China
| | - Ling Qin
- Department of Hematology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
| | - Qinan Yin
- School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, China.
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15
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Poddar A, Rao SR, Prithviraj P, Kannourakis G, Jayachandran A. Crosstalk between Immune Checkpoint Modulators, Metabolic Reprogramming and Cellular Plasticity in Triple-Negative Breast Cancer. Curr Oncol 2022; 29:6847-6863. [PMID: 36290817 PMCID: PMC9601266 DOI: 10.3390/curroncol29100540] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/16/2022] [Accepted: 09/21/2022] [Indexed: 01/13/2023] Open
Abstract
Breast cancer is one of the major causes of mortality in women worldwide. Accounting for 15-20% of all breast cancer diagnoses, the triple-negative breast cancer (TNBC) subtype presents with an aggressive clinical course, heightened metastatic potential and the poorest short-term prognosis. TNBC does not respond to hormonal therapy, only partially responds to radio- and chemotherapy, and has limited targeted therapy options, thus underlining the critical need for better therapeutic treatments. Although immunotherapy based on immune checkpoint inhibition is emerging as a promising treatment option for TNBC patients, activation of cellular plasticity programs such as metabolic reprogramming (MR) and epithelial-to-mesenchymal transition (EMT) causes immunotherapy to fail. In this report, we review the role of MR and EMT in immune checkpoint dysregulation in TNBCs and specifically shed light on development of novel combination treatment modalities for this challenging disease. We highlight the clinical relevance of crosstalk between MR, EMT, and immune checkpoints in TNBCs.
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Affiliation(s)
- Arpita Poddar
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia
- Department of Materials Science and Engineering, Monash University, Melbourne, VIC 3800, Australia
- Ian Potter NanoBiosensing Facility, NanoBiotechnology Research Laboratory (NBRL), School of Science, RMIT University, Melbourne, VIC 3000, Australia
| | - Sushma R. Rao
- Proteomics, Metabolomics and MS-Imaging Facility, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia
| | - Prashanth Prithviraj
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia
- School of Science, Psychology and Sports, Federation University Australia, Ballarat, VIC 3350, Australia
| | - George Kannourakis
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia
- School of Science, Psychology and Sports, Federation University Australia, Ballarat, VIC 3350, Australia
| | - Aparna Jayachandran
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia
- School of Science, Psychology and Sports, Federation University Australia, Ballarat, VIC 3350, Australia
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
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16
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Pereira IC, Mascarenhas IF, Capetini VC, Ferreira PMP, Rogero MM, Torres-Leal FL. Cellular reprogramming, chemoresistance, and dietary interventions in breast cancer. Crit Rev Oncol Hematol 2022; 179:103796. [PMID: 36049616 DOI: 10.1016/j.critrevonc.2022.103796] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 07/16/2022] [Accepted: 08/21/2022] [Indexed: 10/31/2022] Open
Abstract
Breast cancer (BC) diagnosis has been associated with significant risk factors, including family history, late menopause, obesity, poor eating habits, and alcoholism. Despite the advances in the last decades regarding cancer treatment, some obstacles still hinder the effectiveness of therapy. For example, chemotherapy resistance is common in locally advanced or metastatic cancer, reducing treatment options and contributing to mortality. In this review, we provide an overview of BC metabolic changes, including the impact of restrictive diets associated with chemoresistance, the therapeutic potential of the diet on tumor progression, pathways related to metabolic health in oncology, and perspectives on the future in the area of oncological nutrition.
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Affiliation(s)
- Irislene Costa Pereira
- Department of Biophysics and Physiology, Center for Health Sciences, Federal University of Piauí, Teresina, Piauí, Brazil; Metabolic Diseases, Exercise and Nutrition Research Group (DOMEN), Center for Health Sciences, Federal University of Piauí, Teresina, Piauí, Brazil
| | - Isabele Frazão Mascarenhas
- Department of Biophysics and Physiology, Center for Health Sciences, Federal University of Piauí, Teresina, Piauí, Brazil
| | | | - Paulo Michel Pinheiro Ferreira
- Department of Biophysics and Physiology, Center for Health Sciences, Federal University of Piauí, Teresina, Piauí, Brazil
| | - Marcelo Macedo Rogero
- Department of Nutrition, School of Public Health, University of São Paulo, Sao Paulo, Brazil
| | - Francisco Leonardo Torres-Leal
- Department of Biophysics and Physiology, Center for Health Sciences, Federal University of Piauí, Teresina, Piauí, Brazil; Metabolic Diseases, Exercise and Nutrition Research Group (DOMEN), Center for Health Sciences, Federal University of Piauí, Teresina, Piauí, Brazil.
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17
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Lv L, Yang S, Zhu Y, Zhai X, Li S, Tao X, Dong D. Relationship between metabolic reprogramming and drug resistance in breast cancer. Front Oncol 2022; 12:942064. [PMID: 36059650 PMCID: PMC9434120 DOI: 10.3389/fonc.2022.942064] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
Breast cancer is the leading cause of cancer death in women. At present, chemotherapy is the main method to treat breast cancer in addition to surgery and radiotherapy, but the process of chemotherapy is often accompanied by the development of drug resistance, which leads to a reduction in drug efficacy. Furthermore, mounting evidence indicates that drug resistance is caused by dysregulated cellular metabolism, and metabolic reprogramming, including enhanced glucose metabolism, fatty acid synthesis and glutamine metabolic rates, is one of the hallmarks of cancer. Changes in metabolism have been considered one of the most important causes of resistance to treatment, and knowledge of the mechanisms involved will help in identifying potential treatment deficiencies. To improve women's survival outcomes, it is vital to elucidate the relationship between metabolic reprogramming and drug resistance in breast cancer. This review analyzes and investigates the reprogramming of metabolism and resistance to breast cancer therapy, and the results offer promise for novel targeted and cell-based therapies.
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Affiliation(s)
- Linlin Lv
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China
| | - Shilei Yang
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yanna Zhu
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiaohan Zhai
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shuai Li
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xufeng Tao
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Deshi Dong
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
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18
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Khajah MA, Khushaish S, Luqmani YA. Glucose deprivation reduces proliferation and motility, and enhances the anti-proliferative effects of paclitaxel and doxorubicin in breast cell lines in vitro. PLoS One 2022; 17:e0272449. [PMID: 35917304 PMCID: PMC9345370 DOI: 10.1371/journal.pone.0272449] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 07/20/2022] [Indexed: 11/19/2022] Open
Abstract
Background Breast cancer chemotherapy with high dose alkylating agents is severely limited by their collateral toxicity to crucial normal tissues such as immune and gut cells. Taking advantage of the selective dependence of cancer cells on high glucose and combining glucose deprivation with these agents could produce therapeutic synergy. Methods In this study we examined the effect of glucose as well as its deprivation, and antagonism using the non-metabolized analogue 2-deoxy glucose, on the proliferation of several breast cancer cell lines MCF7, MDA-MB-231, YS1.2 and pII and one normal breast cell line, using the MTT assay. Motility was quantitatively assessed using the wound healing assay. Lactate, as the end product of anaerobic glucose metabolism, secreted into culture medium was measured by a biochemical assay. The effect of paclitaxel and doxorubicin on cell proliferation was tested in the absence and presence of low concentrations of glucose using MTT assay. Results In all cell lines, glucose supplementation enhanced while glucose deprivation reduced both their proliferation and motility. Lactate added to the medium could substitute for glucose. The inhibitory effects of paclitaxel and doxorubicin were significantly enhanced when glucose concentration was decreased in the culture medium, requiring 1000-fold lesser concentration to achieve a similar degree of inhibition to that seen in glucose-containing medium. Conclusion Our data show that a synergy was obtained by combining paclitaxel and doxorubicin with glucose reduction to inhibit cancer cell growth, which in vivo, might be achieved by applying a carbohydrate-restricted diet during the limited phase of application of chemotherapy; this could permit a dose reduction of the cytotoxic agents, resulting in greater tolerance and lesser side effects.
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19
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Zhang Q, Li W. Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy. World J Stem Cells 2022; 14:267-286. [PMID: 35662861 PMCID: PMC9136564 DOI: 10.4252/wjsc.v14.i4.267] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/19/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.
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Affiliation(s)
- Qi Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wei Li
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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20
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How previous treatment changes the metabolomic profile in patients with metastatic breast cancer. Arch Gynecol Obstet 2022; 306:2115-2122. [PMID: 35467121 PMCID: PMC9633507 DOI: 10.1007/s00404-022-06558-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 04/01/2022] [Indexed: 01/29/2023]
Abstract
Purpose Metabolites are in the spotlight of attention as promising novel breast cancer biomarkers. However, no study has been conducted concerning changes in the metabolomics profile of metastatic breast cancer patients according to previous therapy. Methods We performed a retrospective, single-center, nonrandomized, partially blinded, treatment-based study. Metastatic breast cancer (MBC) patients were enrolled between 03/2010 and 09/2016 at the beginning of a new systemic therapy. The endogenous metabolites in the plasma samples were analyzed using the AbsoluteIDQ® p180 Kit (Biocrates Life Sciences AG, Innsbruck) a targeted, quality and quantitative-controlled metabolomics approach. The statistical analysis was performed using R package, version 3.3.1. ANOVA was used to statistically assess age differences within groups. Furthermore, we analyzed the CTC status of the patients using the CellSearch™ assay. Results We included 178 patients in our study. Upon dividing the study population according to therapy before study inclusion, we found the following: 4 patients had received no therapy, 165 chemotherapy, and 135 anti-hormonal therapy, 30 with anti-Her2 therapy and 38 had received treatment with bevacizumab. Two metabolites were found to be significantly different, depending on the further therapy of the patients: methionine and serine. Whereas methionine levels were higher in the blood of patients who received an anti-Her2-therapy, serine was lower in patients with endocrine therapy only. Conclusion We identified two metabolites for which concentrations differed significantly depending on previous therapies, which could help to choose the next therapy in patients who have already received numerous different treatments.
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21
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Gu I, Gregory E, Atwood C, Lee SO, Song YH. Exploring the Role of Metabolites in Cancer and the Associated Nerve Crosstalk. Nutrients 2022; 14:nu14091722. [PMID: 35565690 PMCID: PMC9103817 DOI: 10.3390/nu14091722] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/12/2022] [Accepted: 04/15/2022] [Indexed: 02/05/2023] Open
Abstract
Since Otto Warburg's first report on the increased uptake of glucose and lactate release by cancer cells, dysregulated metabolism has been acknowledged as a hallmark of cancer that promotes proliferation and metastasis. Over the last century, studies have shown that cancer metabolism is complex, and by-products of glucose and glutamine catabolism induce a cascade of both pro- and antitumorigenic processes. Some vitamins, which have traditionally been praised for preventing and inhibiting the proliferation of cancer cells, have also been proven to cause cancer progression in a dose-dependent manner. Importantly, recent findings have shown that the nervous system is a key player in tumor growth and metastasis via perineural invasion and tumor innervation. However, the link between cancer-nerve crosstalk and tumor metabolism remains unclear. Here, we discuss the roles of relatively underappreciated metabolites in cancer-nerve crosstalk, including lactate, vitamins, and amino acids, and propose the investigation of nutrients in cancer-nerve crosstalk based on their tumorigenicity and neuroregulatory capabilities. Continued research into the metabolic regulation of cancer-nerve crosstalk will provide a more comprehensive understanding of tumor mechanisms and may lead to the identification of potential targets for future cancer therapies.
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Affiliation(s)
- Inah Gu
- Department of Food Science, Division of Agriculture, University of Arkansas, Fayetteville, AR 72704, USA
| | - Emory Gregory
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR 72701, USA
| | - Casey Atwood
- Department of Food Science, Division of Agriculture, University of Arkansas, Fayetteville, AR 72704, USA
| | - Sun-Ok Lee
- Department of Food Science, Division of Agriculture, University of Arkansas, Fayetteville, AR 72704, USA
| | - Young Hye Song
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR 72701, USA
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22
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Liu H, Xu Q, Xi Y, Ma S, Wang J, Bai L, Han C, He H, Li L. Dynamic transcriptome profiling reveals essential roles of the Receptor Tyrosine Kinases (RTK) family in feather development of duck. Br Poult Sci 2022; 63:605-612. [PMID: 35383522 DOI: 10.1080/00071668.2022.2061839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
1. Chicken primary myoblasts (CPMs) are precursors that form muscle fibres. The proliferation and differentiation of CPMs is an essential stage in muscle development. Previous RNA-seq analysis showed that phosphoglycerate dehydrogenase (PHGDH) is a differentially expressed gene in chicken muscle tissue at different growth stages. Therefore, the following study explored the effect of PHGDH on the proliferation and differentiation of CPMs.2. The effect on the proliferation of CPMs by RT-qPCR, CCK-8, and EdU assays after the overexpression and knockdown of PHGDH was evaluated. RT-qPCR, western blotting, and indirect immunofluorescence were used to detect the effect of PHGDH on the differentiation of the CPMs. The expression was observed at different time points for differentiation induced by the CPMs.3. The results showed that PHGDH significantly promoted proliferation and differentiation in CPMs. The results showed that overexpression of PHGDH significantly upregulated CPM proliferation, while knockdown had the opposite effect. Marker genes showed that overexpression of PHGDH significantly upregulated the expression of P21, MYOG and MYOD genes, significantly downregulated the expression of the MSTN gene and promoted the expression of the MYHC protein. In contrast, PHGDH knockdown had the opposite effect.4. Desmin immunofluorescence analysis of myotube differentiation in primary myoblasts showed that overexpression of PHGDH significantly increased the area of myotube differentiation and promoted the proliferation and differentiation of myoblasts. Knockdown of PHGDH had the opposite effect.5. In summary, PHGDH was shown to play a positive role in regulating myoblast proliferation and differentiation. This provided a theoretical basis for further analysis of the regulatory mechanism of the PHGDH gene in chicken muscle development and for improving poultry production.
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Affiliation(s)
| | - Qian Xu
- Sichuan Agricultural University - Chengdu Campus
| | - Yang Xi
- Sichuan Agricultural University - Chengdu Campus
| | - ShengChao Ma
- Sichuan Agricultural University - Chengdu Campus
| | - Jianmei Wang
- Sichuan Agricultural University - Chengdu Campus
| | - Lili Bai
- Sichuan Agricultural University - Chengdu Campus
| | - Chunchun Han
- Sichuan Agricultural University - Chengdu Campus, College of Animal Science and Technology
| | - Hua He
- Sichuan Agricultural University - Chengdu Campus
| | - Liang Li
- Sichuan Agricultural University, College of Animal Sci & Tech
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23
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Chen L, Wu YL, Ding H, Xie KZ, Zhang T, Zhang GX, Wang JY. PHGDH promotes the proliferation and differentiation of primary chicken myoblasts. Br Poult Sci 2022; 63:581-589. [PMID: 35383521 DOI: 10.1080/00071668.2022.2062221] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
1. Chicken primary myoblasts (CPMs) are precursors that form muscle fibres. The proliferation and differentiation of CPMs is an essential stage in muscle development. Previous RNA-seq analysis showed that phosphoglycerate dehydrogenase (PHGDH) is a differentially expressed gene in chicken muscle tissue at different growth stages. Therefore, the following study explored the effect of PHGDH on the proliferation and differentiation of CPMs.2. The effect on the proliferation of CPMs by RT-qPCR, CCK-8, and EdU assays after the overexpression and knockdown of PHGDH was evaluated. RT-qPCR, western blotting, and indirect immunofluorescence were used to detect the effect of PHGDH on the differentiation of the CPMs. The expression was observed at different time points for differentiation induced by the CPMs.3. The results showed that PHGDH significantly promoted proliferation and differentiation in CPMs. The results showed that overexpression of PHGDH significantly upregulated CPM proliferation, while knockdown had the opposite effect. Marker genes showed that overexpression of PHGDH significantly upregulated the expression of P21, MYOG and MYOD genes, significantly downregulated the expression of the MSTN gene and promoted the expression of the MYHC protein. In contrast, PHGDH knockdown had the opposite effect.4. Desmin immunofluorescence analysis of myotube differentiation in primary myoblasts showed that overexpression of PHGDH significantly increased the area of myotube differentiation and promoted the proliferation and differentiation of myoblasts. Knockdown of PHGDH had the opposite effect.5. In summary, PHGDH was shown to play a positive role in regulating myoblast proliferation and differentiation. This provided a theoretical basis for further analysis of the regulatory mechanism of the PHGDH gene in chicken muscle development and for improving poultry production.
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Affiliation(s)
- L Chen
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China.,Joint International Research Laboratory of Agriculture & Agri-Product Safety, Yangzhou University, Yangzhou 225009, China
| | - Y L Wu
- Joint International Research Laboratory of Agriculture & Agri-Product Safety, Yangzhou University, Yangzhou 225009, China.,College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - H Ding
- Joint International Research Laboratory of Agriculture & Agri-Product Safety, Yangzhou University, Yangzhou 225009, China.,College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - K Z Xie
- Joint International Research Laboratory of Agriculture & Agri-Product Safety, Yangzhou University, Yangzhou 225009, China.,College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - T Zhang
- Joint International Research Laboratory of Agriculture & Agri-Product Safety, Yangzhou University, Yangzhou 225009, China.,College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - G X Zhang
- Joint International Research Laboratory of Agriculture & Agri-Product Safety, Yangzhou University, Yangzhou 225009, China.,College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - J Y Wang
- Joint International Research Laboratory of Agriculture & Agri-Product Safety, Yangzhou University, Yangzhou 225009, China.,College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
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24
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Wang Y, Juan L, Peng J, Wang T, Zang T, Wang Y. Explore potential disease related metabolites based on latent factor model. BMC Genomics 2022; 23:269. [PMID: 35387615 PMCID: PMC8985251 DOI: 10.1186/s12864-022-08504-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 11/17/2022] Open
Abstract
Background In biological systems, metabolomics can not only contribute to the discovery of metabolic signatures for disease diagnosis, but is very helpful to illustrate the underlying molecular disease-causing mechanism. Therefore, identification of disease-related metabolites is of great significance for comprehensively understanding the pathogenesis of diseases and improving clinical medicine. Results In the paper, we propose a disease and literature driven metabolism prediction model (DLMPM) to identify the potential associations between metabolites and diseases based on latent factor model. We build the disease glossary with disease terms from different databases and an association matrix based on the mapping between diseases and metabolites. The similarity of diseases and metabolites is used to complete the association matrix. Finally, we predict potential associations between metabolites and diseases based on the matrix decomposition method. In total, 1,406 direct associations between diseases and metabolites are found. There are 119,206 unknown associations between diseases and metabolites predicted with a coverage rate of 80.88%. Subsequently, we extract training sets and testing sets based on data increment from the database of disease-related metabolites and assess the performance of DLMPM on 19 diseases. As a result, DLMPM is proven to be successful in predicting potential metabolic signatures for human diseases with an average AUC value of 82.33%. Conclusion In this paper, a computational model is proposed for exploring metabolite-disease pairs and has good performance in predicting potential metabolites related to diseases through adequate validation. The results show that DLMPM has a better performance in prioritizing candidate diseases-related metabolites compared with the previous methods and would be helpful for researchers to reveal more information about human diseases.
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Affiliation(s)
- Yongtian Wang
- School of Computer Science, Northwestern Polytechnical University, Xi'an, China. .,Key Laboratory of Big Data Storage and Management Ministry of Industry and Information Technology, Northwestern Polytechnical University, Xi'an, China.
| | - Liran Juan
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Jiajie Peng
- School of Computer Science, Northwestern Polytechnical University, Xi'an, China.,Key Laboratory of Big Data Storage and Management Ministry of Industry and Information Technology, Northwestern Polytechnical University, Xi'an, China
| | - Tao Wang
- School of Computer Science, Northwestern Polytechnical University, Xi'an, China.,Key Laboratory of Big Data Storage and Management Ministry of Industry and Information Technology, Northwestern Polytechnical University, Xi'an, China
| | - Tianyi Zang
- School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China.
| | - Yadong Wang
- School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China.
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25
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Sergeeva OV, Shcherbinina EY, Shomron N, Zatsepin TS. Modulation of RNA Splicing by Oligonucleotides: Mechanisms of Action and Therapeutic Implications. Nucleic Acid Ther 2022; 32:123-138. [PMID: 35166605 DOI: 10.1089/nat.2021.0067] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Dysregulation of RNA splicing causes many diseases and disorders. Several therapeutic approaches have been developed to correct aberrant alternative splicing events for the treatment of cancers and hereditary diseases, including gene therapy and redirecting splicing, using small molecules or splice switching oligonucleotides (SSO). Significant advances in the chemistry and pharmacology of nucleic acid have led to the development of clinically approved SSO drugs for the treatment of spinal muscular dystrophy and Duchenne muscular dystrophy (DMD). In this review, we discuss the mechanisms of SSO action with emphasis on "less common" approaches to modulate alternative splicing, including bipartite and bifunctional SSO, oligonucleotide decoys for splice factors and SSO-mediated mRNA degradation via AS-NMD and NGD pathways. We briefly discuss the current progress and future perspectives of SSO therapy for rare and ultrarare diseases.
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Affiliation(s)
- Olga V Sergeeva
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia
| | | | - Noam Shomron
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Timofei S Zatsepin
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia.,Department of Chemistry, Moscow State University, Moscow, Russia
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26
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Wang G, Wang F, Meng Z, Wang N, Zhou C, Zhang J, Zhao L, Wang G, Shan B. Uncovering potential genes in colorectal cancer based on integrated and DNA methylation analysis in the gene expression omnibus database. BMC Cancer 2022; 22:138. [PMID: 35114976 PMCID: PMC8815138 DOI: 10.1186/s12885-022-09185-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 01/10/2022] [Indexed: 12/19/2022] Open
Abstract
Background Colorectal cancer (CRC) is major cancer-related death. The aim of this study was to identify differentially expressed and differentially methylated genes, contributing to explore the molecular mechanism of CRC. Methods Firstly, the data of gene transcriptome and genome-wide DNA methylation expression were downloaded from the Gene Expression Omnibus database. Secondly, functional analysis of differentially expressed and differentially methylated genes was performed, followed by protein-protein interaction (PPI) analysis. Thirdly, the Cancer Genome Atlas (TCGA) dataset and in vitro experiment was used to validate the expression of selected differentially expressed and differentially methylated genes. Finally, diagnosis and prognosis analysis of selected differentially expressed and differentially methylated genes was performed. Results Up to 1958 differentially expressed (1025 up-regulated and 993 down-regulated) genes and 858 differentially methylated (800 hypermethylated and 58 hypomethylated) genes were identified. Interestingly, some genes, such as GFRA2 and MDFI, were differentially expressed-methylated genes. Purine metabolism (involved IMPDH1), cell adhesion molecules and PI3K-Akt signaling pathway were significantly enriched signaling pathways. GFRA2, FOXQ1, CDH3, CLDN1, SCGN, BEST4, CXCL12, CA7, SHMT2, TRIP13, MDFI and IMPDH1 had a diagnostic value for CRC. In addition, BEST4, SHMT2 and TRIP13 were significantly associated with patients’ survival. Conclusions The identified altered genes may be involved in tumorigenesis of CRC. In addition, BEST4, SHMT2 and TRIP13 may be considered as diagnosis and prognostic biomarkers for CRC patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09185-0.
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Affiliation(s)
- Guanglin Wang
- The Second Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Feifei Wang
- The Second Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zesong Meng
- The Second Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Na Wang
- Institute of Tumor, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chaoxi Zhou
- The Second Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Juan Zhang
- The Second Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lianmei Zhao
- Scientific Research Center, The Fourth Hospital of Hebei Medical University, No. 12, Jiankang Road, Chang'an District, Shijiazhuang, 050010, Hebei Province, China
| | - Guiying Wang
- The Second Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.,Department of General Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Baoen Shan
- Scientific Research Center, The Fourth Hospital of Hebei Medical University, No. 12, Jiankang Road, Chang'an District, Shijiazhuang, 050010, Hebei Province, China.
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27
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Ripoll C, Roldan M, Ruedas-Rama MJ, Orte A, Martin M. Breast Cancer Cell Subtypes Display Different Metabolic Phenotypes That Correlate with Their Clinical Classification. BIOLOGY 2021; 10:biology10121267. [PMID: 34943182 PMCID: PMC8698801 DOI: 10.3390/biology10121267] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/28/2021] [Accepted: 11/29/2021] [Indexed: 12/11/2022]
Abstract
Simple Summary Recent studies on cancer cell metabolism have achieved notable breakthroughs that have led to a new scientific paradigm. How cancer cell metabolic reprogramming is orchestrated and the decisive role of this reprogramming in the oncogenic process and tumor adaptative evolution has been characterized at the molecular level. Despite this knowledge, it is essential to understand how cancer cells can metabolically respond as a living whole to ensure their survival and adaptation potential. In this work, we investigated whether different cancers and different subtypes display different metabolic phenotypes with a focus on breast cancer cell models representative of each clinical subtype. The potential results might have significant translational implications for diagnostic, prognostic and therapeutic applications. Abstract Metabolic reprogramming of cancer cells represents an orchestrated network of evolving molecular and functional adaptations during oncogenic progression. In particular, how metabolic reprogramming is orchestrated in breast cancer and its decisive role in the oncogenic process and tumor evolving adaptations are well consolidated at the molecular level. Nevertheless, potential correlations between functional metabolic features and breast cancer clinical classification still represent issues that have not been fully studied to date. Accordingly, we aimed to investigate whether breast cancer cell models representative of each clinical subtype might display different metabolic phenotypes that correlate with current clinical classifications. In the present work, functional metabolic profiling was performed for breast cancer cell models representative of each clinical subtype based on the combination of enzyme inhibitors for key metabolic pathways, and isotope-labeled tracing dynamic analysis. The results indicated the main metabolic phenotypes, so-called ‘metabophenotypes’, in terms of their dependency on glycolytic metabolism or their reliance on mitochondrial oxidative metabolism. The results showed that breast cancer cell subtypes display different metabophenotypes. Importantly, these metabophenotypes are clearly correlated with the current clinical classifications.
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Affiliation(s)
- Consuelo Ripoll
- Nanoscopy-UGR Laboratory, Departamento de Fisicoquimica, Unidad de Excelencia de Química Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Universidad de Granada, Campus Cartuja, 18071 Granada, Spain; (C.R.); (M.J.R.-R.)
- GENYO, Pfizer-Universidad de Granada-Junta de Andalucia Centre for Genomics and Oncological Research, Avda Ilustracion 114, PTS, 18016 Granada, Spain;
| | - Mar Roldan
- GENYO, Pfizer-Universidad de Granada-Junta de Andalucia Centre for Genomics and Oncological Research, Avda Ilustracion 114, PTS, 18016 Granada, Spain;
- Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias, Universidad de Granada, Avda. Fuentenueva, 18071 Granada, Spain
| | - Maria J. Ruedas-Rama
- Nanoscopy-UGR Laboratory, Departamento de Fisicoquimica, Unidad de Excelencia de Química Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Universidad de Granada, Campus Cartuja, 18071 Granada, Spain; (C.R.); (M.J.R.-R.)
| | - Angel Orte
- Nanoscopy-UGR Laboratory, Departamento de Fisicoquimica, Unidad de Excelencia de Química Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Universidad de Granada, Campus Cartuja, 18071 Granada, Spain; (C.R.); (M.J.R.-R.)
- Correspondence: (A.O.); (M.M.)
| | - Miguel Martin
- GENYO, Pfizer-Universidad de Granada-Junta de Andalucia Centre for Genomics and Oncological Research, Avda Ilustracion 114, PTS, 18016 Granada, Spain;
- Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias, Universidad de Granada, Avda. Fuentenueva, 18071 Granada, Spain
- Correspondence: (A.O.); (M.M.)
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28
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Shin E, Koo JS. Glucose Metabolism and Glucose Transporters in Breast Cancer. Front Cell Dev Biol 2021; 9:728759. [PMID: 34552932 PMCID: PMC8450384 DOI: 10.3389/fcell.2021.728759] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/10/2021] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most common malignancy in women worldwide and is associated with high mortality rates despite the continuously advancing treatment strategies. Glucose is essential for cancer cell metabolism owing to the Warburg effect. During the process of glucose metabolism, various glycolytic metabolites, such as serine and glycine metabolites, are produced and other metabolic pathways, such as the pentose phosphate pathway (PPP), are associated with the process. Glucose is transported into the cell by glucose transporters, such as GLUT. Breast cancer shows high expressions of glucose metabolism-related enzymes and GLUT, which are also related to breast cancer prognosis. Triple negative breast cancer (TNBC), which is a high-grade breast cancer, is especially dependent on glucose metabolism. Breast cancer also harbors various stromal cells such as cancer-associated fibroblasts and immune cells as tumor microenvironment, and there exists a metabolic interaction between these stromal cells and breast cancer cells as explained by the reverse Warburg effect. Breast cancer is heterogeneous, and, consequently, its metabolic status is also diverse, which is especially affected by the molecular subtype, progression stage, and metastatic site. In this review, we will focus on glucose metabolism and glucose transporters in breast cancer, and we will additionally discuss their potential applications as cancer imaging tracers and treatment targets.
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Affiliation(s)
| | - Ja Seung Koo
- Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
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29
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McGinity CL, Palmieri EM, Somasundaram V, Bhattacharyya DD, Ridnour LA, Cheng RYS, Ryan AE, Glynn SA, Thomas DD, Miranda KM, Anderson SK, Lockett SJ, McVicar DW, Wink DA. Nitric Oxide Modulates Metabolic Processes in the Tumor Immune Microenvironment. Int J Mol Sci 2021; 22:7068. [PMID: 34209132 PMCID: PMC8268115 DOI: 10.3390/ijms22137068] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/22/2021] [Accepted: 06/25/2021] [Indexed: 02/07/2023] Open
Abstract
The metabolic requirements and functions of cancer and normal tissues are vastly different. Due to the rapid growth of cancer cells in the tumor microenvironment, distorted vasculature is commonly observed, which creates harsh environments that require rigorous and constantly evolving cellular adaption. A common hallmark of aggressive and therapeutically resistant tumors is hypoxia and hypoxia-induced stress markers. However, recent studies have identified alterations in a wide spectrum of metabolic pathways that dictate tumor behavior and response to therapy. Accordingly, it is becoming clear that metabolic processes are not uniform throughout the tumor microenvironment. Metabolic processes differ and are cell type specific where various factors promote metabolic heterogeneity within the tumor microenvironment. Furthermore, within the tumor, these metabolically distinct cell types can organize to form cellular neighborhoods that serve to establish a pro-tumor milieu in which distant and spatially distinct cellular neighborhoods can communicate via signaling metabolites from stroma, immune and tumor cells. In this review, we will discuss how biochemical interactions of various metabolic pathways influence cancer and immune microenvironments, as well as associated mechanisms that lead to good or poor clinical outcomes.
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Affiliation(s)
- Christopher L. McGinity
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
| | - Erika M. Palmieri
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
| | - Veena Somasundaram
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
| | - Dibyangana D. Bhattacharyya
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
- Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, H91 TK33 Galway, Ireland; (A.E.R.); (S.A.G.)
| | - Lisa A. Ridnour
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
| | - Robert Y. S. Cheng
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
| | - Aideen E. Ryan
- Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, H91 TK33 Galway, Ireland; (A.E.R.); (S.A.G.)
| | - Sharon A. Glynn
- Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, H91 TK33 Galway, Ireland; (A.E.R.); (S.A.G.)
| | - Douglas D. Thomas
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, USA;
| | | | - Stephen K. Anderson
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
| | - Stephen J. Lockett
- Optical Microscopy and Analysis Laboratory, LEIDO Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA;
| | - Daniel W. McVicar
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
| | - David A. Wink
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
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Ghergurovich JM, Lang JD, Levin MK, Briones N, Facista SJ, Mueller C, Cowan AJ, McBride MJ, Rodriguez ESR, Killian A, Dao T, Lamont J, Barron A, Su X, Hendricks WP, Espina V, Von Hoff DD, O’Shaughnessy J, Rabinowitz JD. Local production of lactate, ribose phosphate, and amino acids within human triple-negative breast cancer. MED 2021; 2:736-754. [PMID: 34223403 PMCID: PMC8248508 DOI: 10.1016/j.medj.2021.03.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Upregulated glucose metabolism is a common feature of tumors. Glucose can be broken down by either glycolysis or the oxidative pentose phosphate pathway (oxPPP). The relative usage within tumors of these catabolic pathways remains unclear. Similarly, the extent to which tumors make biomass precursors from glucose, versus take them up from the circulation, is incompletely defined. METHODS We explore human triple negative breast cancer (TNBC) metabolism by isotope tracing with [1,2-13C]glucose, a tracer that differentiates glycolytic versus oxPPP catabolism and reveals glucose-driven anabolism. Patients enrolled in clinical trial NCT03457779 and received IV infusion of [1,2-13C]glucose during core biopsy of their primary TNBC. Tumor samples were analyzed for metabolite labeling by liquid chromatography-mass spectrometry (LC-MS). Genomic and proteomic analyses were performed and related to observed metabolic fluxes. FINDINGS TNBC ferments glucose to lactate, with glycolysis dominant over the oxPPP. Most ribose phosphate is nevertheless produced by oxPPP. Glucose also feeds amino acid synthesis, including of serine, glycine, aspartate, glutamate, proline and glutamine (but not asparagine). Downstream in glycolysis, tumor pyruvate and lactate labeling exceeds that found in serum, indicating that lactate exchange via monocarboxylic transporters is less prevalent in human TNBC compared with most normal tissues or non-small cell lung cancer. CONCLUSIONS Glucose directly feeds ribose phosphate, amino acid synthesis, lactate, and the TCA cycle locally within human breast tumors.
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Affiliation(s)
- Jonathan M. Ghergurovich
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Jessica D. Lang
- Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
| | - Maren K. Levin
- Baylor Scott & White Research Institute, Dallas, TX 75204, USA
| | - Natalia Briones
- Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
| | - Salvatore J. Facista
- Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
| | - Claudius Mueller
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
| | - Alexis J. Cowan
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Matthew J. McBride
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
- Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
| | | | - Aaron Killian
- Baylor Scott & White Research Institute, Dallas, TX 75204, USA
| | - Tuoc Dao
- Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX 75246, USA
| | - Jeffrey Lamont
- Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX 75246, USA
| | - Alison Barron
- Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX 75246, USA
| | - Xiaoyang Su
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901 USA
| | - William P.D. Hendricks
- Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
| | - Virginia Espina
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
| | - Daniel D. Von Hoff
- Molecular Medicine Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
| | - Joyce O’Shaughnessy
- Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX 75246, USA
| | - Joshua D. Rabinowitz
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
- Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
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31
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Geeraerts SL, Heylen E, De Keersmaecker K, Kampen KR. The ins and outs of serine and glycine metabolism in cancer. Nat Metab 2021; 3:131-141. [PMID: 33510397 DOI: 10.1038/s42255-020-00329-9] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 12/04/2020] [Indexed: 01/30/2023]
Abstract
Cancer cells reprogramme their metabolism to support unrestrained proliferation and survival in nutrient-poor conditions. Whereas non-transformed cells often have lower demands for serine and glycine, several cancer subtypes hyperactivate intracellular serine and glycine synthesis and become addicted to de novo production. Copy-number amplifications of serine- and glycine-synthesis genes and genetic alterations in common oncogenes and tumour-suppressor genes enhance serine and glycine synthesis, resulting in high production and secretion of these oncogenesis-supportive metabolites. In this Review, we discuss the contribution of serine and glycine synthesis to cancer progression. By relying on de novo synthesis pathways, cancer cells are able to enhance macromolecule synthesis, neutralize high levels of oxidative stress and regulate methylation and tRNA formylation. Furthermore, we discuss the immunosuppressive potential of serine and glycine, and the essentiality of both amino acids to promoting survival of non-transformed neighbouring cells. Finally, we point to the emerging data proposing moonlighting functions of serine- and glycine-synthesis enzymes and examine promising small molecules targeting serine and glycine synthesis.
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Affiliation(s)
- Shauni L Geeraerts
- Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Elien Heylen
- Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Kim De Keersmaecker
- Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
| | - Kim R Kampen
- Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
- Maastricht University Medical Centre, Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht, The Netherlands.
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32
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Wang L, Zhang S, Wang X. The Metabolic Mechanisms of Breast Cancer Metastasis. Front Oncol 2021; 10:602416. [PMID: 33489906 PMCID: PMC7817624 DOI: 10.3389/fonc.2020.602416] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 11/23/2020] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is one of the most common malignancy among women worldwide. Metastasis is mainly responsible for treatment failure and is the cause of most breast cancer deaths. The role of metabolism in the progression and metastasis of breast cancer is gradually being emphasized. However, the regulatory mechanisms that conduce to cancer metastasis by metabolic reprogramming in breast cancer have not been expounded. Breast cancer cells exhibit different metabolic phenotypes depending on their molecular subtypes and metastatic sites. Both intrinsic factors, such as MYC amplification, PIK3CA, and TP53 mutations, and extrinsic factors, such as hypoxia, oxidative stress, and acidosis, contribute to different metabolic reprogramming phenotypes in metastatic breast cancers. Understanding the metabolic mechanisms underlying breast cancer metastasis will provide important clues to develop novel therapeutic approaches for treatment of metastatic breast cancer.
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Affiliation(s)
- Lingling Wang
- Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.,Department of Surgical Oncology and Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shizhen Zhang
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaochen Wang
- Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China
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Geeraerts SL, Kampen KR, Rinaldi G, Gupta P, Planque M, Louros N, Heylen E, De Cremer K, De Brucker K, Vereecke S, Verbelen B, Vermeersch P, Schymkowitz J, Rousseau F, Cassiman D, Fendt SM, Voet A, Cammue BPA, Thevissen K, De Keersmaecker K. Repurposing the Antidepressant Sertraline as SHMT Inhibitor to Suppress Serine/Glycine Synthesis-Addicted Breast Tumor Growth. Mol Cancer Ther 2021; 20:50-63. [PMID: 33203732 PMCID: PMC7611204 DOI: 10.1158/1535-7163.mct-20-0480] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/19/2020] [Accepted: 11/03/2020] [Indexed: 11/16/2022]
Abstract
Metabolic rewiring is a hallmark of cancer that supports tumor growth, survival, and chemotherapy resistance. Although normal cells often rely on extracellular serine and glycine supply, a significant subset of cancers becomes addicted to intracellular serine/glycine synthesis, offering an attractive drug target. Previously developed inhibitors of serine/glycine synthesis enzymes did not reach clinical trials due to unfavorable pharmacokinetic profiles, implying that further efforts to identify clinically applicable drugs targeting this pathway are required. In this study, we aimed to develop therapies that can rapidly enter the clinical practice by focusing on drug repurposing, as their safety and cost-effectiveness have been optimized before. Using a yeast model system, we repurposed two compounds, sertraline and thimerosal, for their selective toxicity against serine/glycine synthesis-addicted breast cancer and T-cell acute lymphoblastic leukemia cell lines. Isotope tracer metabolomics, computational docking, enzymatic assays, and drug-target interaction studies revealed that sertraline and thimerosal inhibit serine/glycine synthesis enzymes serine hydroxymethyltransferase and phosphoglycerate dehydrogenase, respectively. In addition, we demonstrated that sertraline's antiproliferative activity was further aggravated by mitochondrial inhibitors, such as the antimalarial artemether, by causing G1-S cell-cycle arrest. Most notably, this combination also resulted in serine-selective antitumor activity in breast cancer mouse xenografts. Collectively, this study provides molecular insights into the repurposed mode-of-action of the antidepressant sertraline and allows to delineate a hitherto unidentified group of cancers being particularly sensitive to treatment with sertraline. Furthermore, we highlight the simultaneous inhibition of serine/glycine synthesis and mitochondrial metabolism as a novel treatment strategy for serine/glycine synthesis-addicted cancers.
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Affiliation(s)
- Shauni Lien Geeraerts
- Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
- Centre of Microbial and Plant Genetics - Plant Fungi Interactions (CMPG-PFI), KU Leuven, Heverlee, Belgium
| | - Kim Rosalie Kampen
- Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
- Maastricht University Medical Center, Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht, the Netherlands
| | - Gianmarco Rinaldi
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB Leuven, Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Purvi Gupta
- Department of Chemistry, KU Leuven, Heverlee, Belgium
| | - Mélanie Planque
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB Leuven, Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Nikolaos Louros
- Switch Laboratory, VIB Center for Brain and Disease Research, VIB-KU Leuven, Leuven, Belgium
- Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Elien Heylen
- Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Kaat De Cremer
- Centre of Microbial and Plant Genetics - Plant Fungi Interactions (CMPG-PFI), KU Leuven, Heverlee, Belgium
| | - Katrijn De Brucker
- Centre of Microbial and Plant Genetics - Plant Fungi Interactions (CMPG-PFI), KU Leuven, Heverlee, Belgium
| | - Stijn Vereecke
- Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Benno Verbelen
- Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Pieter Vermeersch
- Department of Cardiovascular Sciences, University Hospitals Leuven, Leuven, Belgium
| | - Joost Schymkowitz
- Switch Laboratory, VIB Center for Brain and Disease Research, VIB-KU Leuven, Leuven, Belgium
- Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Frederic Rousseau
- Switch Laboratory, VIB Center for Brain and Disease Research, VIB-KU Leuven, Leuven, Belgium
- Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - David Cassiman
- Department of Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Sarah-Maria Fendt
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB Leuven, Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Arnout Voet
- Department of Chemistry, KU Leuven, Heverlee, Belgium
| | - Bruno P A Cammue
- Centre of Microbial and Plant Genetics - Plant Fungi Interactions (CMPG-PFI), KU Leuven, Heverlee, Belgium
| | - Karin Thevissen
- Centre of Microbial and Plant Genetics - Plant Fungi Interactions (CMPG-PFI), KU Leuven, Heverlee, Belgium.
| | - Kim De Keersmaecker
- Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
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Shafei MA, Flemban A, Daly C, Kendrick P, White P, Dean S, Qualtrough D, Conway ME. Differential expression of the BCAT isoforms between breast cancer subtypes. Breast Cancer 2020; 28:592-607. [PMID: 33367952 PMCID: PMC8065012 DOI: 10.1007/s12282-020-01197-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 11/19/2020] [Indexed: 01/08/2023]
Abstract
Background Biological characterisation of breast cancer subtypes is essential as it informs treatment regimens especially as different subtypes have distinct locoregional patterns. This is related to metabolic phenotype, where altered cellular metabolism is a fundamental adaptation of cancer cells during rapid proliferation. In this context, the metabolism of the essential branched-chain amino acids (BCAAs), catalysed by the human branched-chain aminotransferase proteins (hBCAT), offers multiple benefits for tumour growth. Upregulation of the cytosolic isoform of hBCAT (hBCATc), regulated by c-Myc, has been demonstrated to increase cell migration, tumour aggressiveness and proliferation in gliomas, ovarian and colorectal cancer but the importance of the mitochondrial isoform, hBCATm has not been fully investigated. Methods Using immunohistochemistry, the expression profile of metabolic proteins (hBCAT, IDH) was assessed between breast cancer subtypes, HER2 + , luminal A, luminal B and TNBC. Correlations between the percentage and the intensity of protein expression/co-expression with clinical parameters, such as hormone receptor status, tumour stage, lymph-node metastasis and survival, were determined. Results We show that hBCATc expression was found to be significantly associated with the more aggressive HER2 + and luminal B subtypes, whilst hBCATm and IDH1 associated with luminal A subtype. This was concomitant with better prognosis indicating a differential metabolic reliance between these two subtypes, in which enhanced expression of IDH1 may replenish the α-ketoglutarate pool in cells with increased hBCATm expression. Conclusion The cytosolic isoform of BCAT is associated with tumours that express HER2 receptors, whereas the mitochondrial isoform is highly expressed in tumours that are ER + , indicating that the BCAT proteins are regulated through different signalling pathways, which may lead to the identification of novel targets for therapeutic applications targeting dysregulated cancer metabolism.
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Affiliation(s)
- Mai Ahmed Shafei
- Faculty of Health and Life Sciences, University of the West of England, Coldharbour Lane, Bristol, BS16 1QY, UK
| | - Arwa Flemban
- Faculty of Health and Life Sciences, University of the West of England, Coldharbour Lane, Bristol, BS16 1QY, UK.,Department of Pathology, Faculty of Medicine, Umm Al-Qura University, Makkah, 24382, Saudi Arabia
| | - Carl Daly
- Faculty of Health and Life Sciences, University of the West of England, Coldharbour Lane, Bristol, BS16 1QY, UK
| | - Paul Kendrick
- Faculty of Health and Life Sciences, University of the West of England, Coldharbour Lane, Bristol, BS16 1QY, UK
| | - Paul White
- Faculty of Health and Life Sciences, University of the West of England, Coldharbour Lane, Bristol, BS16 1QY, UK
| | - Sarah Dean
- Faculty of Health and Life Sciences, University of the West of England, Coldharbour Lane, Bristol, BS16 1QY, UK
| | - David Qualtrough
- Faculty of Health and Life Sciences, University of the West of England, Coldharbour Lane, Bristol, BS16 1QY, UK
| | - Myra E Conway
- Faculty of Health and Life Sciences, University of the West of England, Coldharbour Lane, Bristol, BS16 1QY, UK.
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Zhang J, Wang E, Zhang L, Zhou B. PSPH induces cell autophagy and promotes cell proliferation and invasion in the hepatocellular carcinoma cell line Huh7 via the AMPK/mTOR/ULK1 signaling pathway. Cell Biol Int 2020; 45:305-319. [PMID: 33079432 DOI: 10.1002/cbin.11489] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 10/12/2020] [Accepted: 10/17/2020] [Indexed: 12/17/2022]
Abstract
Phosphoserine phosphatase (PSPH), a key enzyme of the l-serine synthesis pathway, has been involved in cancer progression and survival. However, limited evidence revealed the PSPH influence on hepatocellular carcinoma (HCC). Herein, we observed that PSPH expression was upregulated in both HCC tissues and cell lines, which was determined by western blotting. TCGA database showed that the PSPH protein levels were significantly upregulated and affected patient survival rates in HCC. Then gain- and loss-of-function manipulations were performed by transfection with a pcDNA-PSPH expression vector or a specific short interfering RNA against PSPH in Huh7 cells. Huh7 cell proliferation, stemness, invasion, and apoptosis were assessed by using CCK-8 test, colony formation assay, Transwell assay, and Flow cytometry analysis, respectively, and levels of autophagy-related proteins were detected by using western blotting. The results showed that PSPH could induce Huh7 cell autophagy, promote cell proliferation and invasion, and inhibit apoptosis. The knockdown of PSPH could inhibit Huh7 cell proliferation, invasion, and autophagy. Furthermore, PSPH activated Liver kinase B1 (LKB1) and TGF beta-activated kinase 1 (TAK1), affected the adenosine 5'-monophosphate-activated protein kinase (AMPK)/mTOR/ULK1 signaling pathway, but could not activate calcium/calmodulin-dependent protein kinase kinase (CaMKK) in Huh7 cells. Inhibition of either LKB1, TAK1, or AMPK could eliminate the effect of PSPH overexpression on Huh7 cell behaviors. However, inhibition of CaMKK could not influence the effect of PSPH overexpression on Huh7 cell behaviors. In conclusion, PSPH could induce autophagy, promote proliferation and invasion, and inhibit apoptosis in HCC cells via the AMPK/mTOR/ULK1 signaling pathway.
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Affiliation(s)
- Jianli Zhang
- The Second General Surgery Department, Xi'an Central Hospital, Xi'an, China
| | - Erhao Wang
- Department of Medicine, Institute for DNA and its Products, Xi'an, China
| | - Lei Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Bo Zhou
- Digestive System Department, The Second Affiliand Hospital of Zhengzhou University, Zhengzhou, China
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36
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Zhang D, Xu X, Ye Q. Metabolism and immunity in breast cancer. Front Med 2020; 15:178-207. [PMID: 33074528 DOI: 10.1007/s11684-020-0793-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 04/17/2020] [Indexed: 12/12/2022]
Abstract
Breast cancer is one of the most common malignancies that seriously threaten women's health. In the process of the malignant transformation of breast cancer, metabolic reprogramming and immune evasion represent the two main fascinating characteristics of cancer and facilitate cancer cell proliferation. Breast cancer cells generate energy through increased glucose metabolism. Lipid metabolism contributes to biological signal pathways and forms cell membranes except energy generation. Amino acids act as basic protein units and metabolic regulators in supporting cell growth. For tumor-associated immunity, poor immunogenicity and heightened immunosuppression cause breast cancer cells to evade the host's immune system. For the past few years, the complex mechanisms of metabolic reprogramming and immune evasion are deeply investigated, and the genes involved in these processes are used as clinical therapeutic targets for breast cancer. Here, we review the recent findings related to abnormal metabolism and immune characteristics, regulatory mechanisms, their links, and relevant therapeutic strategies.
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Affiliation(s)
- Deyu Zhang
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, 100850, China
| | - Xiaojie Xu
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, 100850, China.
| | - Qinong Ye
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, 100850, China.
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37
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Kansara S, Pandey V, Lobie PE, Sethi G, Garg M, Pandey AK. Mechanistic Involvement of Long Non-Coding RNAs in Oncotherapeutics Resistance in Triple-Negative Breast Cancer. Cells 2020; 9:cells9061511. [PMID: 32575858 PMCID: PMC7349003 DOI: 10.3390/cells9061511] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/17/2020] [Accepted: 06/19/2020] [Indexed: 02/07/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is one of the most lethal forms of breast cancer (BC), with a significant disease burden worldwide. Chemoresistance and lack of targeted therapeutics are major hindrances to effective treatments in the clinic and are crucial causes of a worse prognosis and high rate of relapse/recurrence in patients diagnosed with TNBC. In the last decade, long non-coding RNAs (lncRNAs) have been found to perform a pivotal role in most cellular functions. The aberrant functional expression of lncRNAs plays an ever-increasing role in the progression of diverse malignancies, including TNBC. Therefore, lncRNAs have been recently studied as predictors and modifiers of chemoresistance. Our review discusses the potential involvement of lncRNAs in drug-resistant mechanisms commonly found in TNBC and highlights various therapeutic strategies to target lncRNAs in this malignancy.
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Affiliation(s)
- Samarth Kansara
- Amity Institute of Biotechnology, Amity University Haryana, Panchgaon, Manesar, Haryana 122413, India;
| | - Vijay Pandey
- Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518005, China; (V.P.); (P.E.L.)
- Shenzhen Bay Laboratory, Shenzhen 518055, China
| | - Peter E. Lobie
- Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518005, China; (V.P.); (P.E.L.)
- Shenzhen Bay Laboratory, Shenzhen 518055, China
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- Correspondence: (G.S.); (A.K.P.)
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Sector-125, Noida 201313, India;
| | - Amit Kumar Pandey
- Amity Institute of Biotechnology, Amity University Haryana, Panchgaon, Manesar, Haryana 122413, India;
- Correspondence: (G.S.); (A.K.P.)
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38
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Li R, Wang L, Wang X, Geng RX, Li N, Liu XH. Identification of hub genes associated with outcome of clear cell renal cell carcinoma. Oncol Lett 2020; 19:2846-2860. [PMID: 32218839 PMCID: PMC7068649 DOI: 10.3892/ol.2020.11389] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 12/05/2019] [Indexed: 12/17/2022] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is one of the most common tumor types of the urinary system. Bioinformatics tools have been used to identify new biomarkers of ccRCC and to explore the mechanisms underlying development and progression of ccRCC. The present study analyzed the differentially expressed genes (DEGs) associated with RCC using data obtained from Gene Expression Omnibus datasets and GEO2R software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of these DEGs was performed and analyzed using the Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes to identify the hub genes, defined as the genes with the highest degree of interrelation. Subsequently, differential expression and survival analyses of hub genes was performed using The Cancer Genome Atlas database and Gene Expression Profiling Interactive Analysis (GEPIA) online tool. Using GEO2R, 1,650 DEGs were identified, including 743 upregulated and 907 downregulated genes. GO and KEGG pathway analyses indicated that the upregulated DEGs were primarily involved in blood vessel and vasculature development, whereas downregulated DEGs were primarily involved in organic acid metabolic processes and carboxylic acid metabolic processes. Subsequently, important modules were identified in the PPI network using Cytoscape's Molecular Complex Detection. The 15 most connected hub genes were identified among DEGs, including glycine decarboxylase (GLDC), enolase 2 (ENO2) and topoisomerase II alpha. GEPIA revealed the association between expression levels of hub genes and survival. Specifically, GLDC and ENO2 were associated with the prognosis of patients with RCC and thus, the effects of GLDC and ENO2 involvement in renal cancer were investigated in vitro. GLDC and ENO2 affected the proliferation and apoptosis of renal cancer cells. These hub genes may reveal a new mechanism underlying development or progression of RCC and identify new markers for its diagnosis and prognosis.
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Affiliation(s)
- Rengui Li
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Lei Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Xiao Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Rong-Xin Geng
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Ning Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Xiu-Heng Liu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Li X, Zhang K, Hu Y, Luo N. ERRα activates SHMT2 transcription to enhance the resistance of breast cancer to lapatinib via modulating the mitochondrial metabolic adaption. Biosci Rep 2020; 40:BSR20192465. [PMID: 31894856 PMCID: PMC6970080 DOI: 10.1042/bsr20192465] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 12/24/2019] [Accepted: 12/27/2019] [Indexed: 12/14/2022] Open
Abstract
Lapatinib, a tyrosine kinase inhibitor, can initially benefit the patients with breast tumors but fails in later treatment due to the inevitable development of drug resistance. Estrogen-related receptor α (ERRα) modulates the metabolic adaptations in lapatinib-resistant cancer cells; however, the underlying mechanism remains unclear. ERRα was predicted to bind to the serine hydroxymethyltransferase 2 (SHMT2) transcription initiation site in the ER- and HER2-positive cell line BT-474; thus, we hypothesize that ERRα might modulate the resistance of breast cancer to lapatinib via regulating SHMT2. In the present study, we revealed that 2.5 and 5 µM lapatinib treatment could significantly decrease the expression and protein levels of ERRα and SHMT2; ERRα and SHMT2 expression and protein levels were significantly up-regulated in breast cancer cells, in particularly in breast cancer cells with resistance to lapatinib. ERRα knockdown restored the inhibitory effects of lapatinib on the BT-474R cell viability and migration; in the meantime, ERRα knockdown rescued the production of reactive oxygen species (ROS) whereas decreased the ratio of glutathione (GSH)/oxidized glutathione (GSSG) upon lapatinib treatment. Via targeting SHMT2 promoter region, ERRα activated the transcription of SHMT2. The effects of ERRα knockdown on BT-474R cells under lapatinib treatment could be significantly reversed by SHMT2 overexpression. In conclusion, ERRα knockdown suppresses the detoxification and the mitochondrial metabolic adaption in breast cancer resistant to lapatinib; ERRα activates SHMT2 transcription via targeting its promoter region, therefore enhancing breast cancer resistance to lapatinib.
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Affiliation(s)
- Xin Li
- Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Kejing Zhang
- Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yu Hu
- Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Na Luo
- Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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40
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Wu W, Zhong J, Chen J, Niu P, Ding Y, Han S, Xu J, Dai L. Prognostic and Therapeutic Significance of Adhesion-regulating Molecule 1 in Estrogen Receptor-positive Breast Cancer. Clin Breast Cancer 2019; 20:131-144.e3. [PMID: 31669266 DOI: 10.1016/j.clbc.2019.07.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 07/11/2019] [Accepted: 07/27/2019] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Adhesion-regulating molecule 1 (ADRM1) is a polyubiquitin receptor on the 26S proteasome. ADRM1 is upregulated in many cancers. In this study, we evaluated the potential prognostic and predictive value of ADRM1 in breast cancer. MATERIALS AND METHODS Individual and pooled survival analyses were performed on 19 independent breast cancer microarray datasets. Gene signatures enriched by ADRM1 were also analyzed in pooled datasets. RESULTS Gene set enrichment analysis revealed that high expression of ADRM1 was significantly associated with aggressive breast cancer. Our findings revealed that ADRM1 mRNA levels were significantly associated with estrogen receptor (ER) status, progesterone receptor status, tumor size, lymph node status, histologic grade, and molecular subtypes. We also found that higher mRNA ADRM1 expression was significantly correlated with poor survival in patients with breast cancer. The prognostic power of ADRM1 mRNA was similar to the 70-gene wound response genes and 21 gene recurrence score; it was superior to TNM staging. The prognostic value of ADRM1 was better in ER-positive (ER+) breast cancer cases than in ER-negative breast cancer cases. In cases involving stage II breast cancer, radiotherapy significantly reduced the relative risk of OS in the ADRM1-low subgroup. CONCLUSION ADRM1 mRNA levels were significantly related to poor outcome in our breast cancer sample population. It could serve as a prognostic biomarker, especially in ER+ breast cancer and Luminal A breast cancer cases, as well as a predictive biomarker for ER+ breast cancer.
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Affiliation(s)
- Wanbo Wu
- Department of General Surgery, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, Zhejiang Province, China
| | - Jing Zhong
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, Zhejiang Province, China.
| | - Jing Chen
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, Zhejiang Province, China
| | - Pingping Niu
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, Zhejiang Province, China
| | - Yunfeng Ding
- Department of General Surgery, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, Zhejiang Province, China
| | - Shuwen Han
- Department of Medical Oncology, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, Zhejiang Province, China
| | - Jiewei Xu
- Department of General Surgery, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, Zhejiang Province, China
| | - Licheng Dai
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, Zhejiang Province, China
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Wang Y, Zhang S, Yang L, Yang S, Tian Y, Ma Q. Measurement of Conditional Relatedness Between Genes Using Fully Convolutional Neural Network. Front Genet 2019; 10:1009. [PMID: 31695723 PMCID: PMC6818468 DOI: 10.3389/fgene.2019.01009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 09/23/2019] [Indexed: 11/13/2022] Open
Abstract
Measuring conditional relatedness, the degree of relation between a pair of genes in a certain condition, is a basic but difficult task in bioinformatics, as traditional co-expression analysis methods rely on co-expression similarities, well known with high false positive rate. Complement with prior-knowledge similarities is a feasible way to tackle the problem. However, classical combination machine learning algorithms fail in detection and application of the complex mapping relations between similarities and conditional relatedness, so a powerful predictive model will have enormous benefit for measuring this kind of complex mapping relations. To this need, we propose a novel deep learning model of convolutional neural network with a fully connected first layer, named fully convolutional neural network (FCNN), to measure conditional relatedness between genes using both co-expression and prior-knowledge similarities. The results on validation and test datasets show FCNN model yields an average 3.0% and 2.7% higher accuracy values for identifying gene–gene interactions collected from the COXPRESdb, KEGG, and TRRUST databases, and a benchmark dataset of Xiao-Yong et al. research, by grid-search 10-fold cross validation, respectively. In order to estimate the FCNN model, we conduct a further verification on the GeneFriends and DIP datasets, and the FCNN model obtains an average of 1.8% and 7.6% higher accuracy, respectively. Then the FCNN model is applied to construct cancer gene networks, and also calls more practical results than other compared models and methods. A website of the FCNN model and relevant datasets can be accessed from https://bmbl.bmi.osumc.edu/FCNN.
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Affiliation(s)
- Yan Wang
- Key Laboratory of Symbol Computation and Knowledge Engineering of Ministry of Education, College of Computer Science and Technology, Jilin University, Changchun, China.,School of Artificial Intelligence, Jilin University, Changchun, China
| | - Shuangquan Zhang
- Key Laboratory of Symbol Computation and Knowledge Engineering of Ministry of Education, College of Computer Science and Technology, Jilin University, Changchun, China
| | - Lili Yang
- Department of Obstetrics, The First Hospital of Jilin University, Changchun, China
| | - Sen Yang
- Key Laboratory of Symbol Computation and Knowledge Engineering of Ministry of Education, College of Computer Science and Technology, Jilin University, Changchun, China
| | - Yuan Tian
- School of Artificial Intelligence, Jilin University, Changchun, China
| | - Qin Ma
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, United States
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Wei L, Lee D, Law CT, Zhang MS, Shen J, Chin DWC, Zhang A, Tsang FHC, Wong CLS, Ng IOL, Wong CCL, Wong CM. Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC. Nat Commun 2019; 10:4681. [PMID: 31615983 PMCID: PMC6794322 DOI: 10.1038/s41467-019-12606-7] [Citation(s) in RCA: 261] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 09/17/2019] [Indexed: 02/07/2023] Open
Abstract
Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common. By using genome-wide CRISPR/Cas9 library screening, we identify phosphoglycerate dehydrogenase (PHGDH), the first committed enzyme in the serine synthesis pathway (SSP), as a critical driver for Sorafenib resistance. Sorafenib treatment activates SSP by inducing PHGDH expression. With RNAi knockdown and CRISPR/Cas9 knockout models, we show that inactivation of PHGDH paralyzes the SSP and reduce the production of αKG, serine, and NADPH. Concomitantly, inactivation of PHGDH elevates ROS level and induces HCC apoptosis upon Sorafenib treatment. More strikingly, treatment of PHGDH inhibitor NCT-503 works synergistically with Sorafenib to abolish HCC growth in vivo. Similar findings are also obtained in other FDA-approved tyrosine kinase inhibitors (TKIs), including Regorafenib or Lenvatinib. In summary, our results demonstrate that targeting PHGDH is an effective approach to overcome TKI drug resistance in HCC. Resistance to the tyrosine kinase inhibitor Sorafenib, which is the standard treatment for advanced hepatocellular carcinoma, is a major clinical challenge. Here, the authors show that phosphoglycerate dehydrogenase, a key enzyme in the serine synthesis pathway, drives sorafenib resistance.
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Affiliation(s)
- Lai Wei
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong.,Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Derek Lee
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong.,Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Cheuk-Ting Law
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong.,Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Misty Shuo Zhang
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong.,Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Jialing Shen
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong.,Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Don Wai-Ching Chin
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong.,Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Allen Zhang
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong.,Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Felice Ho-Ching Tsang
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong.,Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Ceci Lok-Sze Wong
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong.,Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Irene Oi-Lin Ng
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong.,Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Carmen Chak-Lui Wong
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong. .,Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
| | - Chun-Ming Wong
- State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong. .,Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
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Snezhkina AV, Lukyanova EN, Fedorova MS, Kalinin DV, Melnikova NV, Stepanov OA, Kiseleva MV, Kaprin AD, Pudova EA, Kudryavtseva AV. Novel Genes Associated with the Development of Carotid Paragangliomas. Mol Biol 2019. [DOI: 10.1134/s0026893319040137] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Alshabi AM, Shaikh IA, Vastrad C. Exploring the Molecular Mechanism of the Drug-Treated Breast Cancer Based on Gene Expression Microarray. Biomolecules 2019; 9:biom9070282. [PMID: 31311202 PMCID: PMC6681318 DOI: 10.3390/biom9070282] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 06/24/2019] [Accepted: 07/09/2019] [Indexed: 02/07/2023] Open
Abstract
: Breast cancer (BRCA) remains the leading cause of cancer morbidity and mortality worldwide. In the present study, we identified novel biomarkers expressed during estradiol and tamoxifen treatment of BRCA. The microarray dataset of E-MTAB-4975 from Array Express database was downloaded, and the differential expressed genes (DEGs) between estradiol-treated BRCA sample and tamoxifen-treated BRCA sample were identified by limma package. The pathway and gene ontology (GO) enrichment analysis, construction of protein-protein interaction (PPI) network, module analysis, construction of target genes-miRNA interaction network and target genes-transcription factor (TF) interaction network were performed using bioinformatics tools. The expression, prognostic values, and mutation of hub genes were validated by SurvExpress database, cBioPortal, and human protein atlas (HPA) database. A total of 856 genes (421 up-regulated genes and 435 down-regulated genes) were identified in T47D (overexpressing Split Ends (SPEN) + estradiol) samples compared to T47D (overexpressing Split Ends (SPEN) + tamoxifen) samples. Pathway and GO enrichment analysis revealed that the DEGs were mainly enriched in response to lysine degradation II (pipecolate pathway), cholesterol biosynthesis pathway, cell cycle pathway, and response to cytokine pathway. DEGs (MCM2, TCF4, OLR1, HSPA5, MAP1LC3B, SQSTM1, NEU1, HIST1H1B, RAD51, RFC3, MCM10, ISG15, TNFRSF10B, GBP2, IGFBP5, SOD2, DHF and MT1H) , which were significantly up- and down-regulated in estradiol and tamoxifen-treated BRCA samples, were selected as hub genes according to the results of protein-protein interaction (PPI) network, module analysis, target genes-miRNA interaction network and target genes-TF interaction network analysis. The SurvExpress database, cBioPortal, and Human Protein Atlas (HPA) database further confirmed that patients with higher expression levels of these hub genes experienced a shorter overall survival. A comprehensive bioinformatics analysis was performed, and potential therapeutic applications of estradiol and tamoxifen were predicted in BRCA samples. The data may unravel the future molecular mechanisms of BRCA.
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Affiliation(s)
- Ali Mohamed Alshabi
- Department of Clinical Pharmacy, College of Pharmacy, Najran University, Najran, 66237, Saudi Arabia
| | - Ibrahim Ahmed Shaikh
- Department of Pharmacology, College of Pharmacy, Najran University, Najran, 66237, Saudi Arabia
| | - Chanabasayya Vastrad
- Biostatistics and Bioinformatics, ChanabasavaNilaya, Bharthinagar, Dharwad 580001, Karnataka, India.
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Mikó E, Kovács T, Sebő É, Tóth J, Csonka T, Ujlaki G, Sipos A, Szabó J, Méhes G, Bai P. Microbiome-Microbial Metabolome-Cancer Cell Interactions in Breast Cancer-Familiar, but Unexplored. Cells 2019; 8:E293. [PMID: 30934972 PMCID: PMC6523810 DOI: 10.3390/cells8040293] [Citation(s) in RCA: 135] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 03/22/2019] [Accepted: 03/26/2019] [Indexed: 12/18/2022] Open
Abstract
Breast cancer is a leading cause of death among women worldwide. Dysbiosis, an aberrant composition of the microbiome, characterizes breast cancer. In this review we discuss the changes to the metabolism of breast cancer cells, as well as the composition of the breast and gut microbiome in breast cancer. The role of the breast microbiome in breast cancer is unresolved, nevertheless it seems that the gut microbiome does have a role in the pathology of the disease. The gut microbiome secretes bioactive metabolites (reactivated estrogens, short chain fatty acids, amino acid metabolites, or secondary bile acids) that modulate breast cancer. We highlight the bacterial species or taxonomical units that generate these metabolites, we show their mode of action, and discuss how the metabolites affect mitochondrial metabolism and other molecular events in breast cancer. These metabolites resemble human hormones, as they are produced in a "gland" (in this case, the microbiome) and they are subsequently transferred to distant sites of action through the circulation. These metabolites appear to be important constituents of the tumor microenvironment. Finally, we discuss how bacterial dysbiosis interferes with breast cancer treatment through interfering with chemotherapeutic drug metabolism and availability.
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Affiliation(s)
- Edit Mikó
- Department of Medical Chemistry, University of Debrecen, 4032 Debrecen, Hungary.
- Department of Microbiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
| | - Tünde Kovács
- Department of Medical Chemistry, University of Debrecen, 4032 Debrecen, Hungary.
| | - Éva Sebő
- Kenézy Breast Center, Kenézy Gyula County Hospital, 4032 Debrecen, Hungary.
| | - Judit Tóth
- Kenézy Breast Center, Kenézy Gyula County Hospital, 4032 Debrecen, Hungary.
| | - Tamás Csonka
- Department of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
| | - Gyula Ujlaki
- Department of Medical Chemistry, University of Debrecen, 4032 Debrecen, Hungary.
| | - Adrienn Sipos
- Department of Medical Chemistry, University of Debrecen, 4032 Debrecen, Hungary.
| | - Judit Szabó
- Department of Microbiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
| | - Gábor Méhes
- Department of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
| | - Péter Bai
- Department of Medical Chemistry, University of Debrecen, 4032 Debrecen, Hungary.
- MTA-DE Lendület Laboratory of Cellular Metabolism, 4032 Debrecen, Hungary.
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
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Eniu DT, Romanciuc F, Moraru C, Goidescu I, Eniu D, Staicu A, Rachieriu C, Buiga R, Socaciu C. The decrease of some serum free amino acids can predict breast cancer diagnosis and progression. Scandinavian Journal of Clinical and Laboratory Investigation 2019; 79:17-24. [PMID: 30880483 DOI: 10.1080/00365513.2018.1542541] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This study was targeted on a metabolomic approach to compare the blood serum free amino acid profiles and concentration of confirmed breast cancer (stages I-III) patients to healthy controls in order to establish reliable biomarkers of early detection and prediction of breast cancer. The ultra-high-performance liquid chromatography coupled with mass spectrometry using positive ionization electrospray was applied for the picoline-derivatized serum free amino acids using the EZ:faastTM kit. Multivariate statistical analysis principal component analysis, partial least squares discrimination analysis and univariate analysis were applied in order to discriminate between patient groups and putative amino acid biomarkers for breast cancer. A significant decrease of amino acid concentrations between the breast cancer group and the control group was positively correlated with breast cancer progression. Arginine, Alanine, Isoleucine, Tyrosine and Tryptophan were identified as being good potential discriminants (AUROC ≥0.85) and suitable candidates to diagnose and predict the breast cancer progression.
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Affiliation(s)
- Dan Tudor Eniu
- a Department of Surgical Oncology , Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Florina Romanciuc
- b University of Agricultural Sciences and Veterinary Medicine , Department of Biotechnologies Cluj-Napoca , Romania.,c RTD Center for Applied Biotechnology in Diagnosis and Molecular Therapy, Cluj-Napoca, Romania
| | - Corina Moraru
- c RTD Center for Applied Biotechnology in Diagnosis and Molecular Therapy, Cluj-Napoca, Romania
| | - Iulian Goidescu
- d 1st Department of Obstetrics and Gynecology , Iuliu Haţieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Daniela Eniu
- e Department of Biophysics , Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Adelina Staicu
- d 1st Department of Obstetrics and Gynecology , Iuliu Haţieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Claudiu Rachieriu
- a Department of Surgical Oncology , Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Rareş Buiga
- f Department of Pathology , Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Carmen Socaciu
- b University of Agricultural Sciences and Veterinary Medicine , Department of Biotechnologies Cluj-Napoca , Romania.,c RTD Center for Applied Biotechnology in Diagnosis and Molecular Therapy, Cluj-Napoca, Romania
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Lin C, Zhang Y, Chen Y, Bai Y, Zhang Y. Long noncoding RNA LINC01234 promotes serine hydroxymethyltransferase 2 expression and proliferation by competitively binding miR-642a-5p in colon cancer. Cell Death Dis 2019; 10:137. [PMID: 30755591 PMCID: PMC6372696 DOI: 10.1038/s41419-019-1352-4] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 12/26/2018] [Accepted: 01/07/2019] [Indexed: 01/06/2023]
Abstract
Long noncoding RNAs (lncRNAs) have been indicated as important regulators in various human cancers. However, the overall biological roles and clinical significance of most lncRNAs in colon carcinogenesis are not fully understood. Hence, we investigated the clinical significance, biological function and mechanism of LINC01234 in colon cancer. First, we analyzed LINC01234 alterations in colon cancer tissues and corresponding paracancerous tissues through the analysis of sequencing data obtained from The Cancer Genome Atlas and colon cancer patients. Next, we evaluated the effect of LINC01234 on colon cancer cell proliferation and its regulatory mechanism of serine hydroxymethyltransferase 2 (SHMT2) by acting as a competing endogenous RNA (ceRNA). We found that LINC01234 expression was significantly upregulated in colon cancer tissues and was associated with a shorter survival time. Furthermore, the knockdown of LINC01234 induced proliferation arrest via suppressing serine/glycine metabolism. Mechanistic investigations have indicated that LINC01234 functions as a ceRNA for miR-642a-5p, thereby leading to the derepression of its endogenous target serine hydroxymethyltransferase 2 (SHMT2). LINC01234 is significantly overexpressed in colon cancer, and the LINC01234–miR642a-5p–SHMT2 axis plays a critical role in colon cancer proliferation. Our findings may provide a potential new target for colon cancer diagnosis and therapy.
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Affiliation(s)
- Changwei Lin
- Department of Gastrointestinal surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan, 410013, China.,College of Life Sciences, Central South University, Changsha, Hunan, 410078, China
| | - Yi Zhang
- Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, 221000, Xuzhou, P.R. China
| | - Yifei Chen
- Department of Otolaryngology-Head Neck Surgery, The Fourth Hospital of Changsha (The Changsha Affiliated Hospital of Hunan Normal University), Hunan Normal University, Changsha, Hunan, 410013, China
| | - Yang Bai
- Department of Gastrointestinal surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan, 410013, China
| | - Yi Zhang
- Department of Gastrointestinal surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan, 410013, China.
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Saad MA, Ku J, Kuo SZ, Li PX, Zheng H, Yu MA, Wang-Rodriguez J, Ongkeko WM. Identification and characterization of dysregulated P-element induced wimpy testis-interacting RNAs in head and neck squamous cell carcinoma. Oncol Lett 2019; 17:2615-2622. [PMID: 30854037 PMCID: PMC6365962 DOI: 10.3892/ol.2019.9913] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 06/20/2018] [Indexed: 01/08/2023] Open
Abstract
It is clear that alcohol consumption is a major risk factor in the pathogenesis of head and neck squamous cell carcinoma (HNSCC); however, the molecular mechanism underlying the pathogenesis of alcohol-associated HNSCC remains poorly understood. The aim of the present study was to identify and characterize P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) and PIWI proteins dysregulated in alcohol-associated HNSCC to elucidate their function in the development of this cancer. Using next generation RNA-sequencing (RNA-seq) data obtained from 40 HNSCC patients, the piRNA and PIWI protein expression of HNSCC samples was compared between alcohol drinkers and non-drinkers. A separate piRNA expression RNA-seq analysis of 18 non-smoker HNSCC patients was also conducted. To verify piRNA expression, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed on the most differentially expressed alcohol-associated piRNAs in ethanol and acetaldehyde-treated normal oral keratinocytes. The correlation between piRNA expression and patient survival was analyzed using Kaplan-Meier estimators and multivariate Cox proportional hazard models. A comparison between alcohol drinking and non-drinking HNSCC patients demonstrated that a panel of 3,223 piRNA transcripts were consistently detected and differentially expressed. RNA-seq analysis and in vitro RT-qPCR verification revealed that 4 of these piRNAs, piR-35373, piR-266308, piR-58510 and piR-38034, were significantly dysregulated between drinking and non-drinking cohorts. Of these four piRNAs, low expression of piR-58510 and piR-35373 significantly correlated with improved patient survival. Furthermore, human PIWI-like protein 4 was consistently upregulated in ethanol and acetaldehyde-treated normal oral keratinocytes. These results demonstrate that alcohol consumption may cause dysregulation of piRNA expression in HNSCC and in vitro verifications identified 4 piRNAs that may be involved in the pathogenesis of alcohol-associated HNSCC.
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Affiliation(s)
- Maarouf A Saad
- School of Medicine, Yale University, New Haven, CT 06510, USA
| | - Jonjei Ku
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA
| | - Selena Z Kuo
- School of Medicine, University of California, San Francisco, CA 94143, USA
| | - Pin Xue Li
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA
| | - Hao Zheng
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA
| | - Michael Andrew Yu
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA
| | - Jessica Wang-Rodriguez
- Veterans Administration Medical Center and Department of Pathology, University of California, San Diego, La Jolla, CA 92161, USA
| | - Weg M Ongkeko
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA
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Babourina-Brooks B, Kohe S, Gill SK, MacPherson L, Wilson M, Davies NP, Peet AC. Glycine: a non-invasive imaging biomarker to aid magnetic resonance spectroscopy in the prediction of survival in paediatric brain tumours. Oncotarget 2018; 9:18858-18868. [PMID: 29721167 PMCID: PMC5922361 DOI: 10.18632/oncotarget.24789] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 02/25/2018] [Indexed: 11/25/2022] Open
Abstract
Paediatric brain tumours have a high mortality rate and are the most common solid tumour of childhood. Identification of high risk patients may allow for better treatment stratification. Magnetic Resonance Spectroscopy (MRS) provides a non-invasive measure of brain tumour metabolism and quantifies metabolite survival markers to aid in the clinical management of patients. Glycine can be identified using MRS and has been recently found to be important for cancer cell proliferation in tumours making it a valuable prognostic marker. The aims of this study were to investigate glycine and its added value to MRS as a prognostic marker for paediatric brain tumours in a clinical setting. 116 children with newly diagnosed brain tumours were examined with short echo-time MRS at the Birmingham Children’s Hospital and followed up for five years. Survival analysis was performed using Cox regression on the entire metabolite basis set with focus on glycine and three other established survival markers for comparison: n-acetylaspartate, scyllo-inositol and lipids at 1.3 ppm. Multivariate Cox regression was used in conjunction with risk values to establish if glycine added prognostic power when combined to the established survival markers. Glycine was found to be a marker of poor prognosis in the cohort (p < 0.05) and correlated with tumour grade (p < 0.01). The addition of glycine improved the prognostic power of MRS compared to using the combination of established survival markers alone. Tumour glycine was found to improve the MRS prediction of reduced survival in paediatric brain tumours aiding the non-invasive assessment of these children.
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Affiliation(s)
- Ben Babourina-Brooks
- School of Cancer and Genomic Sciences, University of Birmingham, Birmingham UK.,Birmingham Children's Hospital NHS foundation Trust, Birmingham, UK
| | - Sarah Kohe
- School of Cancer and Genomic Sciences, University of Birmingham, Birmingham UK.,Birmingham Children's Hospital NHS foundation Trust, Birmingham, UK
| | - Simrandip K Gill
- School of Cancer and Genomic Sciences, University of Birmingham, Birmingham UK.,Birmingham Children's Hospital NHS foundation Trust, Birmingham, UK
| | | | - Martin Wilson
- Centre for Human Brain Health, School of Psychology, University of Birmingham, Birmingham, UK
| | - Nigel P Davies
- Medical Physics and Imaging, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Andrew C Peet
- School of Cancer and Genomic Sciences, University of Birmingham, Birmingham UK.,Birmingham Children's Hospital NHS foundation Trust, Birmingham, UK
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Cha YJ, Kim ES, Koo JS. Amino Acid Transporters and Glutamine Metabolism in Breast Cancer. Int J Mol Sci 2018; 19:E907. [PMID: 29562706 PMCID: PMC5877768 DOI: 10.3390/ijms19030907] [Citation(s) in RCA: 115] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 03/15/2018] [Accepted: 03/18/2018] [Indexed: 01/04/2023] Open
Abstract
Amino acid transporters are membrane transport proteins, most of which are members of the solute carrier families. Amino acids are essential for the survival of all types of cells, including tumor cells, which have an increased demand for nutrients to facilitate proliferation and cancer progression. Breast cancer is the most common malignancy in women worldwide and is still associated with high mortality rates, despite improved treatment strategies. Recent studies have demonstrated that the amino acid metabolic pathway is altered in breast cancer and that amino acid transporters affect tumor growth and progression. In breast cancer, glutamine is one of the key nutrients, and glutamine metabolism is closely related to the amino acid transporters. In this review, we focus on amino acid transporters and their roles in breast cancer. We also highlight the different subsets of upregulated amino acid transporters in breast cancer and discuss their potential applications as treatment targets, cancer imaging tracers, and drug delivery components. Glutamine metabolism as well as its regulation and therapeutic implication in breast cancer are also discussed.
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Affiliation(s)
- Yoon Jin Cha
- Department of Pathology, Yonsei University College of Medicine, Seoul, 03722, Korea.
| | - Eun-Sol Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, 03722, Korea.
| | - Ja Seung Koo
- Department of Pathology, Yonsei University College of Medicine, Seoul, 03722, Korea.
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