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1
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Kaimuangpak K, Lehtonen M, Rautio J, Weerapreeyakul N. Unraveled cancer cell survival-associated amino acid metabolism of HepG2 cells altered by Thai rat-tailed radish microgreen extract examined by untargeted LC-MS/MS analysis. Food Chem 2025; 474:143206. [PMID: 39954416 DOI: 10.1016/j.foodchem.2025.143206] [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: 07/25/2024] [Revised: 02/02/2025] [Accepted: 02/02/2025] [Indexed: 02/17/2025]
Abstract
Thai rat-tailed radish (RS) microgreens are enriched in macro- and micronutrients and phytochemicals with anticancer potential. This study investigates the antiproliferative effects of RS in the liver HepG2 cell model and untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics analysis. RS was partitioned in water and dichloromethane (DCM). DCM was collected and evaporated to yield crude extract. The extract exhibited antiproliferation with inhibitory concentrations (IC50) of 612.5 ± 24.7 μg/ml at 24 h and 568.6 ± 11.0 μg/ml at 48 h. Metabolic pathways relevant to the anticancer effects are amino acid metabolism, including (1) alanine, aspartate, and glutamate metabolism; (2) nicotinate and nicotinamide metabolism; and (3) cysteine and methionine metabolism. Significantly, glutamine was upregulated, and aspartic acid, NAD, 5'-methylthioadenosine, cystathionine, and S-adenosylhomocysteine were downregulated. This finding suggested plausible effects of RS on liver cancer cell survival and invasion activities.
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Affiliation(s)
- Karnchanok Kaimuangpak
- Graduate School (in the program of Research and Development in Pharmaceuticals), Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Marko Lehtonen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, 70211, Finland.
| | - Jarkko Rautio
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, 70211, Finland.
| | - Natthida Weerapreeyakul
- Division of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.
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2
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Saez-Carrion E, Aguilar-Aragon M, García-López L, Dominguez M, Uribe ML. Metabolic Adaptations in Cancer and the Host Using Drosophila Models and Advanced Tools. Cells 2024; 13:1977. [PMID: 39682725 PMCID: PMC11640731 DOI: 10.3390/cells13231977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 10/31/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
Cancer is a multifactorial process involving genetic, epigenetic, physiological, and metabolic changes. The ability of tumours to regulate new reactive pathways is essential for their survival. A key aspect of this involves the decision-making process of cancer cells as they balance the exploitation of surrounding and distant tissues for their own benefit while avoiding the rapid destruction of the host. Nutrition plays a central role in these processes but is inherently limited. Understanding how tumour cells interact with non-tumoural tissues to acquire nutrients is crucial. In this review, we emphasise the utility of Drosophila melanogaster as a model organism for dissecting the complex oncogenic networks underlying these interactions. By studying various levels-from individual tumour cells to systemic markers-we can gain new insights into how cancer adapts and thrives. Moreover, developing innovative technologies, such as high-throughput methods and metabolic interventions, enhances our ability to explore how tumours adapt to different conditions. These technological advances allow us to explore tumour adaptations and open new opportunities for potential therapeutic strategies.
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Affiliation(s)
- Ernesto Saez-Carrion
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Miguel Hernández (UMH), Campus de Sant Joan, 03550 Sant Joan d’Alacant, Spain; (M.A.-A.); (L.G.-L.); (M.D.)
| | - Mario Aguilar-Aragon
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Miguel Hernández (UMH), Campus de Sant Joan, 03550 Sant Joan d’Alacant, Spain; (M.A.-A.); (L.G.-L.); (M.D.)
| | - Lucia García-López
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Miguel Hernández (UMH), Campus de Sant Joan, 03550 Sant Joan d’Alacant, Spain; (M.A.-A.); (L.G.-L.); (M.D.)
- Faculty of Health Sciences, Universidad Europea de Valencia, 03016 Alicante, Spain
| | - Maria Dominguez
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Miguel Hernández (UMH), Campus de Sant Joan, 03550 Sant Joan d’Alacant, Spain; (M.A.-A.); (L.G.-L.); (M.D.)
| | - Mary Luz Uribe
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Miguel Hernández (UMH), Campus de Sant Joan, 03550 Sant Joan d’Alacant, Spain; (M.A.-A.); (L.G.-L.); (M.D.)
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3
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Bayat M, Golestani S, Motlaghzadeh S, Bannazadeh Baghi H, Lalehzadeh A, Sadri Nahand J. War or peace: Viruses and metastasis. Biochim Biophys Acta Rev Cancer 2024; 1879:189179. [PMID: 39299491 DOI: 10.1016/j.bbcan.2024.189179] [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: 06/10/2024] [Revised: 09/04/2024] [Accepted: 09/07/2024] [Indexed: 09/22/2024]
Abstract
Metastasis, the dissemination of malignant cells from a primary tumor to secondary sites, poses a catastrophic burden to cancer treatment and is the predominant cause of mortality in cancer patients. Metastasis as one of the main aspects of cancer progression could be strongly under the influence of viral infections. In fact, viruses have been central to modern cancer research and are associated with a great number of cancer cases. Viral-encoded elements are involved in modulating essential pathways or specific targets that are implicated in different stages of metastasis. Considering the continuous emergence of new viruses and the establishment of their contribution to cancer progression, the warfare between viruses and cancer appears to be endless. Here we aimed to review the critical mechanism and pathways involved in cancer metastasis and the influence of viral machinery and various routes that viruses adopt to manipulate those pathways for their benefit.
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Affiliation(s)
- Mobina Bayat
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahin Golestani
- Department of ophthalmology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Motlaghzadeh
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Bannazadeh Baghi
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aidin Lalehzadeh
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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4
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Subramanian D, Ponnusamy Manogaran G, Dharmadurai D. A systematic review on the impact of micro-nanoplastics on human health: Potential modulation of epigenetic mechanisms and identification of biomarkers. CHEMOSPHERE 2024; 363:142986. [PMID: 39094707 DOI: 10.1016/j.chemosphere.2024.142986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/29/2024] [Accepted: 07/30/2024] [Indexed: 08/04/2024]
Abstract
Epigenetic-mediated modifications, induced by adverse environmental conditions, significantly alter an organism's physiological mechanisms. Even after elimination of the stimulus, these epigenetic modifications can be inherited through mitosis, thereby triggering transgenerational epigenetics. Plastics, with their versatile properties, are indispensable in various aspects of daily life. However, due to mismanagement, plastics have become so ubiquitous in the environment that no ecosystem on Earth is free from micro-nanoplastics (MNPs). This situation has raised profound concerns regarding their potential impact on human health. Recently, both in vivo animal and in vitro human cellular models have shown the potential to identify the harmful effects of MNPs at the genome level. The emerging epigenetic impact of MNP exposure is characterized by short-term alterations in chromatin remodelling and miRNA modulation. However, to understand long-term epigenetic changes and potential transgenerational effects, substantial and more environmentally realistic exposure studies are needed. In the current review, the intricate epigenetic responses, including the NHL-2-EKL-1, NDK-1-KSR1/2, and WRT-3-ASP-2 cascades, wnt-signalling, and TGF- β signalling, established in model organisms such as C. elegans, mice, and human cell lines upon exposure to MNPs, were systematically examined. This comprehensive analysis aimed to predict human pathways by identifying human homologs using databases and algorithms. We are confident that various parallel miRNA pathways, specifically the KSR-ERK-MAPK pathway, FOXO-Insulin cascade, and GPX3-HIF-α in humans, may be influenced by MNP exposure. This influence may lead to disruptions in key metabolic and immune pathways, including glucose balance, apoptosis, cell proliferation, and angiogenesis. Therefore, we believe that these genes and pathways could serve as potential biomarkers for future studies. Additionally, this review emphasizes the origin, dispersion, and distribution of plastics, providing valuable insights into the complex relationship between plastics and human health while elaborating on the epigenetic impacts.
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Affiliation(s)
- Darshini Subramanian
- Department of Biotechnology, School of Applied Sciences, REVA University, Bengaluru, 560064, Karnataka, India.
| | | | - Dhanasekaran Dharmadurai
- Department of Microbiology, Bharathidasan University, Tiruchirappalli, 620024, Tamil Nadu, India.
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5
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Saini V, Do Y, Yam JWP, Wong YH. Elevated extracellular vesicular Nm23-H1 subdues the pro-migratory potential of breast cancer cell-derived extracellular vesicles. Cell Signal 2024; 120:111203. [PMID: 38723736 DOI: 10.1016/j.cellsig.2024.111203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 04/19/2024] [Accepted: 05/01/2024] [Indexed: 05/12/2024]
Abstract
Metastasis is a key determinant in cancer mortality which is often associated with decreased levels of Nm23-H1, a well-established metastasis suppressor. Despite lacking a secretion signal peptide, Nm23-H1 has been reported to be present in the extracellular space and enclosed within extracellular vesicles (EVs). While the presence of Nm23-H1 proteins in EVs released by cancer cells has been observed through proteomics profiling, the role of vesicular Nm23-H1 remains unclear. Here, we investigated the function of vesicular Nm23-H1 using MDA-MB-231 (highly metastatic, low Nm23-H1) and MCF-7 (low/non-metastatic, high Nm23-H1) breast cancer cell models. Our findings confirm that Nm23-H1 is indeed encapsulated within EVs, and its levels can be manipulated through overexpression and knockdown approaches. Functional assays revealed that EVs derived from MDA-MB-231 cells that contained high levels of Nm23-H1 exhibit impaired pro-migratory properties, suggesting that vesicular Nm23-H1 may act as a metastasis suppressor. Furthermore, EVs with increased levels of Nm23-H1 altered the transcript levels of multiple cancer-related genes in recipient cells and stimulated type I interferon signaling through STAT1 phosphorylation. These results suggest the existence of an unconventional signaling pathway mediated by the uptake of EVs enriched with Nm23-H1, which may contribute to the anti-metastatic effect of Nm23-H1 in the tumor microenvironment. Additionally, our study demonstrates that elevated Nm23-H1 levels can impact the abundance of various other proteins encapsulated within breast cancer cell-derived EVs, such as SUSD2 (Sushi Domain Containing 2) which can also modulate metastasis.
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Affiliation(s)
- Vasu Saini
- Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, China
| | - Yelim Do
- Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, China
| | - Judy Wai Ping Yam
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yung Hou Wong
- Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, China; State Key Laboratory of Molecular Neuroscience and the Molecular Neuroscience Center, Hong Kong University of Science and Technology, Hong Kong, China.
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6
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Gary CR, Acharige NPN, Oyewumi TO, Pflum MKH. Kinase-catalyzed biotinylation for discovery and validation of substrates to multispecificity kinases NME1 and NME2. J Biol Chem 2024; 300:107588. [PMID: 39032654 PMCID: PMC11375270 DOI: 10.1016/j.jbc.2024.107588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 06/28/2024] [Accepted: 07/01/2024] [Indexed: 07/23/2024] Open
Abstract
Protein phosphorylation by kinases regulates mammalian cell functions, such as growth, division, and signal transduction. Among human kinases, NME1 and NME2 are associated with metastatic tumor suppression but remain understudied due to the lack of tools to monitor their cellular substrates. In particular, NME1 and NME2 are multispecificity kinases phosphorylating serine, threonine, histidine, and aspartic acid residues of substrate proteins, and the heat and acid sensitivity of phosphohistidine and phosphoaspartate complicates substrate discovery and validation. To provide new substrate monitoring tools, we established the γ-phosphate-modified ATP analog, ATP-biotin, as a cosubstrate for phosphorylbiotinylation of NME1 and NME2 cellular substrates. Building upon this ATP-biotin compatibility, the Kinase-catalyzed Biotinylation with Inactivated Lysates for Discovery of Substrates method enabled validation of a known substrate and the discovery of seven NME1 and three NME2 substrates. Given the paucity of methods to study kinase substrates, ATP-biotin and the Kinase-catalyzed Biotinylation with Inactivated Lysates for Discovery of Substrates method are valuable tools to characterize the roles of NME1 and NME2 in human cell biology.
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Affiliation(s)
- Chelsea R Gary
- Department of Chemistry, Wayne State University, Detroit, Michigan, USA
| | | | | | - Mary Kay H Pflum
- Department of Chemistry, Wayne State University, Detroit, Michigan, USA.
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7
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Ning J, Sala M, Reina J, Kalagiri R, Hunter T, McCullough BS. Histidine Phosphorylation: Protein Kinases and Phosphatases. Int J Mol Sci 2024; 25:7975. [PMID: 39063217 PMCID: PMC11277029 DOI: 10.3390/ijms25147975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 07/09/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
Phosphohistidine (pHis) is a reversible protein post-translational modification (PTM) that is currently poorly understood. The P-N bond in pHis is heat and acid-sensitive, making it more challenging to study than the canonical phosphoamino acids pSer, pThr, and pTyr. As advancements in the development of tools to study pHis have been made, the roles of pHis in cells are slowly being revealed. To date, a handful of enzymes responsible for controlling this modification have been identified, including the histidine kinases NME1 and NME2, as well as the phosphohistidine phosphatases PHPT1, LHPP, and PGAM5. These tools have also identified the substrates of these enzymes, granting new insights into previously unknown regulatory mechanisms. Here, we discuss the cellular function of pHis and how it is regulated on known pHis-containing proteins, as well as cellular mechanisms that regulate the activity of the pHis kinases and phosphatases themselves. We further discuss the role of the pHis kinases and phosphatases as potential tumor promoters or suppressors. Finally, we give an overview of various tools and methods currently used to study pHis biology. Given their breadth of functions, unraveling the role of pHis in mammalian systems promises radical new insights into existing and unexplored areas of cell biology.
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Affiliation(s)
- Jia Ning
- Correspondence: (J.N.); (B.S.M.)
| | | | | | | | | | - Brandon S. McCullough
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; (M.S.); (J.R.); (R.K.); (T.H.)
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8
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Gelman IH. Metastasis suppressor genes in clinical practice: are they druggable? Cancer Metastasis Rev 2023; 42:1169-1188. [PMID: 37749308 PMCID: PMC11629483 DOI: 10.1007/s10555-023-10135-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 09/01/2023] [Indexed: 09/27/2023]
Abstract
Since the identification of NM23 (now called NME1) as the first metastasis suppressor gene (MSG), a small number of other gene products and non-coding RNAs have been identified that suppress specific parameters of the metastatic cascade, yet which have little or no ability to regulate primary tumor initiation or maintenance. MSG can regulate various pathways or cell biological functions such as those controlling mitogen-activated protein kinase pathway mediators, cell-cell and cell-extracellular matrix protein adhesion, cytoskeletal architecture, G-protein-coupled receptors, apoptosis, and transcriptional complexes. One defining facet of this gene class is that their expression is typically downregulated, not mutated, in metastasis, such that any effective therapeutic intervention would involve their re-expression. This review will address the therapeutic targeting of MSG, once thought to be a daunting task only facilitated by ectopically re-expressing MSG in metastatic cells in vivo. Examples will be cited of attempts to identify actionable oncogenic pathways that might suppress the formation or progression of metastases through the re-expression of specific metastasis suppressors.
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Affiliation(s)
- Irwin H Gelman
- Department of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
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Prunier C, Chavrier P, Boissan M. Mechanisms of action of NME metastasis suppressors - a family affair. Cancer Metastasis Rev 2023; 42:1155-1167. [PMID: 37353690 PMCID: PMC10713741 DOI: 10.1007/s10555-023-10118-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 06/09/2023] [Indexed: 06/25/2023]
Abstract
Metastatic progression is regulated by metastasis promoter and suppressor genes. NME1, the prototypic and first described metastasis suppressor gene, encodes a nucleoside diphosphate kinase (NDPK) involved in nucleotide metabolism; two related family members, NME2 and NME4, are also reported as metastasis suppressors. These proteins physically interact with members of the GTPase dynamin family, which have key functions in membrane fission and fusion reactions necessary for endocytosis and mitochondrial dynamics. Evidence supports a model in which NDPKs provide GTP to dynamins to maintain a high local GTP concentration for optimal dynamin function. NME1 and NME2 are cytosolic enzymes that provide GTP to dynamins at the plasma membrane, which drive endocytosis, suggesting that these NMEs are necessary to attenuate signaling by receptors on the cell surface. Disruption of NDPK activity in NME-deficient tumors may thus drive metastasis by prolonging signaling. NME4 is a mitochondrial enzyme that interacts with the dynamin OPA1 at the mitochondria inner membrane to drive inner membrane fusion and maintain a fused mitochondrial network. This function is consistent with the current view that mitochondrial fusion inhibits the metastatic potential of tumor cells whereas mitochondrial fission promotes metastasis progression. The roles of NME family members in dynamin-mediated endocytosis and mitochondrial dynamics and the intimate link between these processes and metastasis provide a new framework to understand the metastasis suppressor functions of NME proteins.
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Affiliation(s)
- Céline Prunier
- Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, CRSA, Paris, France
| | - Philippe Chavrier
- Actin and Membrane Dynamics Laboratory, Institut Curie - Research Center, CNRS UMR144, PSL Research University, Paris, France
| | - Mathieu Boissan
- Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, CRSA, Paris, France.
- Laboratoire de Biochimie Endocrinienne Et Oncologique, Oncobiologie Cellulaire Et Moléculaire, APHP, Hôpitaux Universitaires Pitié-Salpêtrière-Charles Foix, Paris, France.
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10
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Tan CH, Cheng KW, Park H, Chou TF, Sternberg PW. LINKIN-associated proteins necessary for tissue integrity during collective cell migration. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.08.527750. [PMID: 36798316 PMCID: PMC9934607 DOI: 10.1101/2023.02.08.527750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Cell adhesion plays essential roles in almost every aspect of metazoan biology. LINKIN (Human: ITFG1, Caenorhabditis elegans: lnkn-1) is a conserved transmembrane protein that has been identified to be necessary for tissue integrity during migration. In C. elegans, loss of lnkn-1 results in the detachment of the lead migratory cell from the rest of the developing male gonad. Previously, three interactors of ITFG1/lnkn-1 - RUVBL1/ruvb-1, RUVBL2/ruvb-2, and alpha-tubulin - were identified by immunoprecipitation-mass spectrometry (IP-MS) analysis using human HEK293T cells and then validated in the nematode male gonad. The ITFG1-RUVBL1 interaction has since been independently validated in a breast cancer cell line model that also implicates the involvement of the pair in metastasis. Here, we showed that epitope-tagged ITFG1 localized to the cell surface of MDA-MB-231 breast cancer cells. Using IP-MS analysis, we identified a new list of potential interactors of ITFG1. Loss-of-function analysis of their C. elegans orthologs found that three of the interactors - ATP9A/tat-5, NME1/ndk-1, and ANAPC2/apc-2 - displayed migratory detachment phenotypes similar to that of lnkn-1. Taken together with the other genes whose reduction-of-function phenotype is similar to that of lnkn-1 (notably cohesion and condensin), suggests the involvement of membrane remodeling and chromosome biology in LINKIN-dependent cell adhesion and supports the hypothesis for a structural role of chromosomes in post-mitotic cells.
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Affiliation(s)
- Chieh-Hsiang Tan
- Division of Biology and Biological Engineering, California Institute of Technology
| | - Kai-Wen Cheng
- Division of Biology and Biological Engineering, California Institute of Technology
| | - Heenam Park
- Division of Biology and Biological Engineering, California Institute of Technology
| | - Tsui-Fen Chou
- Division of Biology and Biological Engineering, California Institute of Technology
- Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology
| | - Paul W. Sternberg
- Division of Biology and Biological Engineering, California Institute of Technology
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11
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Liang N, Li C, Zhang N, Xu Q, Zou S, Zhang M, Si S, Zeng L. Effects of NM23 transfection of human gastric carcinoma cells in mice. Open Life Sci 2023; 18:20220610. [PMID: 37250840 PMCID: PMC10224620 DOI: 10.1515/biol-2022-0610] [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: 12/24/2022] [Revised: 03/22/2023] [Accepted: 04/05/2023] [Indexed: 05/31/2023] Open
Abstract
Gastric carcinoma is a frequent malignant tumor worldwide. NM23 plays an important role in pathological processes, including in the occurrence and development of tumors. The purpose of this study is to examine the effect of NM23 transfection of human gastric carcinoma cells (BGC-823) on growth and metastases of BGC-823 abdominal cancer xenografts in nude mice. BGC-823 cells were transfected with an adenovirus vector for NM23 (NM23-OE), transfected with an empty vector (NC), or were not transfected (Ctrl). Eighteen female BALB/c-nu mice were randomly divided into three groups (six per group) according to the type of BGC-823 cells administered by intraperitoneal injection. After 2 weeks, necropsies of mice were performed, abdominal circumferences were measured, and abdominal cavities were searched by ultrasound. In order to observe the xenografts in nude mice, there were gross macroscopic observations and microscopic observations. In addition, immunohistochemical analysis and western blot of NM23 were also performed. Green fluorescence in the NM23-OE and NC cells indicated successful transfection. The multiplicity of infection is 80%. A comparison of the three groups of mice indicated the NM23-OE group had positive conditions (abdominal circumferences: 81.83 ± 2.40 mm), but the other groups had negative conditions and enlarged abdomens (NC: 90.83 ± 2.32 mm; Ctrl: 92.67 ± 2.07 mm). Ultrasound observations confirmed large tumors in the NC and Ctrl groups, but did not find in the NM23-OE group. There were no obvious ascites in the NM23-OE group, but the cytological examination of ascites exfoliation in NC and Ctrl groups indicated that there were large and deep-stained gastric carcinoma cells. Tumor expression of NM23 was greater in the NM23-OE group than in the NC and Ctrl groups (both p < 0.05). In conclusion, transfection of BCG-823 cells with NM23 rather than an empty vector (NC) or no vector (Ctrl) led to reduced growth and metastases of abdominal cancer xenografts in nude mice.
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Affiliation(s)
- Na Liang
- Department of Histology and Embryology, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Chunming Li
- Department of Pathology, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Neng Zhang
- Department of Urology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Qiang Xu
- Department of Urology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Shengnan Zou
- Department of Pathology, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Meng Zhang
- Department of Pathology, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Shuyao Si
- Department of Pathology, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Li Zeng
- Department of Pathology, Zunyi Medical University, Zunyi, Guizhou 563000, China
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12
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Niu ZS, Wang WH, Niu XJ. Recent progress in molecular mechanisms of postoperative recurrence and metastasis of hepatocellular carcinoma. World J Gastroenterol 2022; 28:6433-6477. [PMID: 36569275 PMCID: PMC9782839 DOI: 10.3748/wjg.v28.i46.6433] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 10/31/2022] [Accepted: 11/21/2022] [Indexed: 12/08/2022] Open
Abstract
Hepatectomy is currently considered the most effective option for treating patients with early and intermediate hepatocellular carcinoma (HCC). Unfortunately, the postoperative prognosis of patients with HCC remains unsatisfactory, predominantly because of high postoperative metastasis and recurrence rates. Therefore, research on the molecular mechanisms of postoperative HCC metastasis and recurrence will help develop effective intervention measures to prevent or delay HCC metastasis and recurrence and to improve the long-term survival of HCC patients. Herein, we review the latest research progress on the molecular mechanisms underlying postoperative HCC metastasis and recurrence to lay a foundation for improving the understanding of HCC metastasis and recurrence and for developing more precise prevention and intervention strategies.
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Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Xiao-Jun Niu
- Department of Internal Medicine, Qingdao Shibei District People's Hospital, Qingdao 266033, Shandong Province, China
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Faheem MM, Rahim JU, Ahmad SM, Mir KB, Kaur G, Bhagat M, Rai R, Goswami A. Heterochiral dipeptide d-phenylalanyl- l-phenylalanine (H- D Phe- L Phe-OH) as a potential inducer of metastatic suppressor NM23H1 in p53 wild-type and mutant cells. Mol Carcinog 2022; 61:1143-1160. [PMID: 36239557 DOI: 10.1002/mc.23465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 08/29/2022] [Accepted: 09/08/2022] [Indexed: 12/24/2022]
Abstract
In recent years, significant progress has been made to the use-case of small peptides because of their diversified edifice and hence their versatile application scope in cancer therapy. Here we identify the heterochiral dipeptide H-D Phe-L Phe-OH (F1) as a potent inducer of the metastatic suppressor NM23H1. We divulge the effect of F1 on the major EMT/metastasis-associated genes and the implications on the invasion and migration ability of cancer cells. The anti-invasive potential of F1 was directly correlated with NM23H1 expression. Mechanistically, F1 treatment elevated p53 levels as validated by localization and transcriptional studies. In the NM23H1 knockdown condition, F1 failed to induce any p53 expression/nuclear localization, indicating that the upregulation in p53 expression by F1 is NM23H1 dependent. We also demonstrate how the antimetastatic potential of F1 is primarily mediated through NM23H1 irrespective of the p53 status of the cell. However, both NM23H1 and a functional p53 protein in conjunction govern the apoptotic and cytostatic potential of F1. Coimmunoprecipitation studies unraveled the augmentation of the p53 and NM23H1 interaction in p53 wild-type cells. However, in p53 mutated cells, no such enrichment was evidenced. We employed mouse isogenic cell lines (4T-1 and 4T-1 p53) to determine the in vivo efficacy of F1 (spontaneous and experimental models). Decreased tumor volume in the cohort injected with 4T-1 p53 cells demonstrated that while the antimetastatic potential of F1 was reliant on NM23H1, p53 activation was required for ablation of primary tumor burden. Our findings unravel that F1 treatment induces significant abrogation of the migration, invasion and metastatic potential of both p53 wild-type and p53 deficient cancers mediated through NM23H1.
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Affiliation(s)
- Mir Mohd Faheem
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India.,School of Biotechnology, University of Jammu, Jammu, Jammu and Kashmir, India
| | - Junaid Ur Rahim
- Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India.,Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Syed Mudabir Ahmad
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India.,Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Khalid Bashir Mir
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India.,Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Gursimar Kaur
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India.,Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Madhulika Bhagat
- School of Biotechnology, University of Jammu, Jammu, Jammu and Kashmir, India
| | - Rajkishor Rai
- Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India.,Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Anindya Goswami
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India.,Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
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14
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Yang E, Huang S, Jami-Alahmadi Y, McInerney GM, Wohlschlegel JA, Li MMH. Elucidation of TRIM25 ubiquitination targets involved in diverse cellular and antiviral processes. PLoS Pathog 2022; 18:e1010743. [PMID: 36067236 PMCID: PMC9481182 DOI: 10.1371/journal.ppat.1010743] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 09/16/2022] [Accepted: 07/15/2022] [Indexed: 11/19/2022] Open
Abstract
The tripartite motif (TRIM) family of E3 ubiquitin ligases is well known for its roles in antiviral restriction and innate immunity regulation, in addition to many other cellular pathways. In particular, TRIM25-mediated ubiquitination affects both carcinogenesis and antiviral response. While individual substrates have been identified for TRIM25, it remains unclear how it regulates diverse processes. Here we characterized a mutation, R54P, critical for TRIM25 catalytic activity, which we successfully utilized to "trap" substrates. We demonstrated that TRIM25 targets proteins implicated in stress granule formation (G3BP1/2), nonsense-mediated mRNA decay (UPF1), nucleoside synthesis (NME1), and mRNA translation and stability (PABPC4). The R54P mutation abolishes TRIM25 inhibition of alphaviruses independently of the host interferon response, suggesting that this antiviral effect is a direct consequence of ubiquitination. Consistent with that, we observed diminished antiviral activity upon knockdown of several TRIM25-R54P specific interactors including NME1 and PABPC4. Our findings highlight that multiple substrates mediate the cellular and antiviral activities of TRIM25, illustrating the multi-faceted role of this ubiquitination network in modulating diverse biological processes.
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Affiliation(s)
- Emily Yang
- Molecular Biology Institute, University of California, Los Angeles, California, United States of America
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California, United States of America
| | - Serina Huang
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America
| | - Yasaman Jami-Alahmadi
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America
| | - Gerald M. McInerney
- Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - James A. Wohlschlegel
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America
| | - Melody M. H. Li
- Molecular Biology Institute, University of California, Los Angeles, California, United States of America
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California, United States of America
- AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America
- * E-mail:
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15
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Starska-Kowarska K. Dietary Carotenoids in Head and Neck Cancer-Molecular and Clinical Implications. Nutrients 2022; 14:nu14030531. [PMID: 35276890 PMCID: PMC8838110 DOI: 10.3390/nu14030531] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/07/2022] [Accepted: 01/12/2022] [Indexed: 01/27/2023] Open
Abstract
Head and neck cancer (HNC) is one of the most common cancers in the world according to GLOBCAN. In 2018, it was reported that HNC accounts for approximately 3% of all human cancers (51,540 new cases) and is the cause of nearly 1.5% of all cancer deaths (10,030 deaths). Despite great advances in treatment, HNC is indicated as a leading cause of death worldwide. In addition to having a positive impact on general health, a diet rich in carotenoids can regulate stages in the course of carcinogenesis; indeed, strong epidemiological associations exist between dietary carotenoids and HNS, and it is presumed that diets with carotenoids can even reduce cancer risk. They have also been proposed as potential chemotherapeutic agents and substances used in chemoprevention of HNC. The present review discusses the links between dietary carotenoids and HNC. It examines the prospective anticancer effect of dietary carotenoids against intracellular cell signalling and mechanisms, oxidative stress regulation, as well as their impact on apoptosis, cell cycle progression, cell proliferation, angiogenesis, metastasis, and chemoprevention; it also provides an overview of the limited preclinical and clinical research published in this arena. Recent epidemiological, key opinion-forming systematic reviews, cross-sectional, longitudinal, prospective, and interventional studies based on in vitro and animal models of HNC also indicate that high carotenoid content obtained from daily supplementation has positive effects on the initiation, promotion, and progression of HNC. This article presents these results according to their increasing clinical credibility.
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Affiliation(s)
- Katarzyna Starska-Kowarska
- Department of Physiology, Pathophysiology and Clinical Immunology, Department of Clinical Physiology, Medical University of Lodz, Żeligowskiego 7/9, 90-752 Lodz, Poland; ; Tel.: +48-604-541-412
- Department of Otorhinolaryngology, EnelMed Center Expert, Lodz, Drewnowska 58, 91-001 Lodz, Poland
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16
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Fierti AO, Yakass MB, Okertchiri EA, Adadey SM, Quaye O. The Role of Epstein-Barr Virus in Modulating Key Tumor Suppressor Genes in Associated Malignancies: Epigenetics, Transcriptional, and Post-Translational Modifications. Biomolecules 2022; 12:biom12010127. [PMID: 35053275 PMCID: PMC8773690 DOI: 10.3390/biom12010127] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/27/2021] [Accepted: 01/05/2022] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV) is ubiquitous and carried by approximately 90% of the world’s adult population. Several mechanisms and pathways have been proposed as to how EBV facilitates the pathogenesis and progression of malignancies, such as Hodgkin’s lymphoma, Burkitt’s lymphoma, nasopharyngeal carcinoma, and gastric cancers, the majority of which have been linked to viral proteins that are expressed upon infection including latent membrane proteins (LMPs) and Epstein-Barr virus nuclear antigens (EBNAs). EBV expresses microRNAs that facilitate the progression of some cancers. Mostly, EBV induces epigenetic silencing of tumor suppressor genes, degradation of tumor suppressor mRNA transcripts, post-translational modification, and inactivation of tumor suppressor proteins. This review summarizes the mechanisms by which EBV modulates different tumor suppressors at the molecular and cellular levels in associated cancers. Briefly, EBV gene products upregulate DNA methylases to induce epigenetic silencing of tumor suppressor genes via hypermethylation. MicroRNAs expressed by EBV are also involved in the direct targeting of tumor suppressor genes for degradation, and other EBV gene products directly bind to tumor suppressor proteins to inactivate them. All these processes result in downregulation and impaired function of tumor suppressors, ultimately promoting malignances.
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17
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Lacombe ML, Lamarche F, De Wever O, Padilla-Benavides T, Carlson A, Khan I, Huna A, Vacher S, Calmel C, Desbourdes C, Cottet-Rousselle C, Hininger-Favier I, Attia S, Nawrocki-Raby B, Raingeaud J, Machon C, Guitton J, Le Gall M, Clary G, Broussard C, Chafey P, Thérond P, Bernard D, Fontaine E, Tokarska-Schlattner M, Steeg P, Bièche I, Schlattner U, Boissan M. The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor. BMC Biol 2021; 19:228. [PMID: 34674701 PMCID: PMC8529772 DOI: 10.1186/s12915-021-01155-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 09/17/2021] [Indexed: 12/11/2022] Open
Abstract
Background Mitochondrial nucleoside diphosphate kinase (NDPK-D, NME4, NM23-H4) is a multifunctional enzyme mainly localized in the intermembrane space, bound to the inner membrane. Results We constructed loss-of-function mutants of NDPK-D, lacking either NDP kinase activity or membrane interaction and expressed mutants or wild-type protein in cancer cells. In a complementary approach, we performed depletion of NDPK-D by RNA interference. Both loss-of-function mutations and NDPK-D depletion promoted epithelial-mesenchymal transition and increased migratory and invasive potential. Immunocompromised mice developed more metastases when injected with cells expressing mutant NDPK-D as compared to wild-type. This metastatic reprogramming is a consequence of mitochondrial alterations, including fragmentation and loss of mitochondria, a metabolic switch from respiration to glycolysis, increased ROS generation, and further metabolic changes in mitochondria, all of which can trigger pro-metastatic protein expression and signaling cascades. In human cancer, NME4 expression is negatively associated with markers of epithelial-mesenchymal transition and tumor aggressiveness and a good prognosis factor for beneficial clinical outcome. Conclusions These data demonstrate NME4 as a novel metastasis suppressor gene, the first localizing to mitochondria, pointing to a role of mitochondria in metastatic dissemination. Supplementary Information The online version contains supplementary material available at 10.1186/s12915-021-01155-5.
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Affiliation(s)
- Marie-Lise Lacombe
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Paris, France
| | - Frederic Lamarche
- Université Grenoble Alpes, INSERM U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy), Grenoble, France
| | - Olivier De Wever
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium
| | | | - Alyssa Carlson
- Molecular Biology and Biochemistry Department, Wesleyan University, Middletown, USA
| | - Imran Khan
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA
| | - Anda Huna
- Cancer Research Center of Lyon, INSERM U1052, CNRS UMR 5286, Léon Bérard Center, Lyon University, Lyon, France
| | - Sophie Vacher
- Unit of Pharmacogenetics, Department of Genetics, Curie Institute, Paris, France
| | - Claire Calmel
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Paris, France
| | - Céline Desbourdes
- Université Grenoble Alpes, INSERM U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy), Grenoble, France
| | - Cécile Cottet-Rousselle
- Université Grenoble Alpes, INSERM U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy), Grenoble, France
| | - Isabelle Hininger-Favier
- Université Grenoble Alpes, INSERM U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy), Grenoble, France
| | - Stéphane Attia
- Université Grenoble Alpes, INSERM U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy), Grenoble, France
| | - Béatrice Nawrocki-Raby
- Reims Champagne Ardenne University, INSERM, P3Cell UMR-S 1250, SFR CAP-SANTE, Reims, France
| | - Joël Raingeaud
- INSERM U1279, Gustave Roussy Institute, Villejuif, France
| | - Christelle Machon
- Cancer Research Center of Lyon, INSERM U1052, CNRS UMR 5286, Léon Bérard Center, Lyon University, Lyon, France
| | - Jérôme Guitton
- Cancer Research Center of Lyon, INSERM U1052, CNRS UMR 5286, Léon Bérard Center, Lyon University, Lyon, France
| | - Morgane Le Gall
- Proteomics Platform 3P5, Paris University, Cochin Institute, INSERM, U1016, CNRS, UMR8104, Paris, France
| | - Guilhem Clary
- Proteomics Platform 3P5, Paris University, Cochin Institute, INSERM, U1016, CNRS, UMR8104, Paris, France
| | - Cedric Broussard
- Proteomics Platform 3P5, Paris University, Cochin Institute, INSERM, U1016, CNRS, UMR8104, Paris, France
| | - Philippe Chafey
- Proteomics Platform 3P5, Paris University, Cochin Institute, INSERM, U1016, CNRS, UMR8104, Paris, France
| | - Patrice Thérond
- AP-HP, CHU Bicêtre, Laboratory of Biochemistry, Le Kremlin-Bicêtre Hospital, Le Kremlin-Bicêtre, France.,EA7537, Paris Saclay University, Châtenay-Malabry, France
| | - David Bernard
- Cancer Research Center of Lyon, INSERM U1052, CNRS UMR 5286, Léon Bérard Center, Lyon University, Lyon, France
| | - Eric Fontaine
- Université Grenoble Alpes, INSERM U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy), Grenoble, France
| | - Malgorzata Tokarska-Schlattner
- Université Grenoble Alpes, INSERM U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy), Grenoble, France
| | - Patricia Steeg
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA
| | - Ivan Bièche
- Unit of Pharmacogenetics, Department of Genetics, Curie Institute, Paris, France
| | - Uwe Schlattner
- Université Grenoble Alpes, INSERM U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA), Institut Universitaire de France (IUF), Grenoble, France.
| | - Mathieu Boissan
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Paris, France. .,AP-HP, Laboratory of Biochemistry and Hormonology, Tenon Hospital, Paris, France.
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18
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Wawruszak A, Halasa M, Okon E, Kukula-Koch W, Stepulak A. Valproic Acid and Breast Cancer: State of the Art in 2021. Cancers (Basel) 2021; 13:3409. [PMID: 34298623 PMCID: PMC8306563 DOI: 10.3390/cancers13143409] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 07/03/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Valproic acid (2-propylpentanoic acid, VPA) is a short-chain fatty acid, a member of the group of histone deacetylase inhibitors (HDIs). VPA has been successfully used in the treatment of epilepsy, bipolar disorders, and schizophrenia for over 50 years. Numerous in vitro and in vivo pre-clinical studies suggest that this well-known anticonvulsant drug significantly inhibits cancer cell proliferation by modulating multiple signaling pathways. Breast cancer (BC) is the most common malignancy affecting women worldwide. Despite significant progress in the treatment of BC, serious adverse effects, high toxicity to normal cells, and the occurrence of multi-drug resistance (MDR) still limit the effective therapy of BC patients. Thus, new agents which improve the effectiveness of currently used methods, decrease the emergence of MDR, and increase disease-free survival are highly needed. This review focuses on in vitro and in vivo experimental data on VPA, applied individually or in combination with other anti-cancer agents, in the treatment of different histological subtypes of BC.
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Affiliation(s)
- Anna Wawruszak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (M.H.); (E.O.); (A.S.)
| | - Marta Halasa
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (M.H.); (E.O.); (A.S.)
| | - Estera Okon
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (M.H.); (E.O.); (A.S.)
| | - Wirginia Kukula-Koch
- Department of Pharmacognosy, Medical University of Lublin, 20-093 Lublin, Poland;
| | - Andrzej Stepulak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (M.H.); (E.O.); (A.S.)
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19
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Dacol EC, Wang S, Chen Y, Lepique AP. The interaction of SET and protein phosphatase 2A as target for cancer therapy. Biochim Biophys Acta Rev Cancer 2021; 1876:188578. [PMID: 34116173 DOI: 10.1016/j.bbcan.2021.188578] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/31/2021] [Accepted: 05/31/2021] [Indexed: 11/16/2022]
Abstract
In cancer cells, tumor suppressor proteins loss-of-function are usually the result of genetic mutations. Protein Phosphatase 2A is a tumor suppressor that inactivates several signaling pathways through removal of phosphate residues important for other proteins stability and/or activation. Different from other tumor suppressors, PP2A is, in many cancer types, inactivated by endogenous inhibitors. In physiological conditions, these inhibitors are important to balance PP2A activity. However, in cancer cells, overexpression of these inhibitors can keep PP2A inactive, resulting in sustained activation of mitogenic signaling pathways and transcription factors, metabolic reprogramming, with the resulting cancer progression and the resistance to anti-cancer therapies. One of these endogenous inhibitors is the protein SET (SE Translocation). SET is a multifunctional protein, which high expression has been associated with several types of cancer, as well as other diseases such as Alzheimer's disease. Disruption of the interaction between SET and PP2A to rescue the activity of PP2A may represent a new therapeutic strategy and opportunity for cancer treatment. This review brings up-to-date advances on the interactions between SET and PP2A and their biological consequences. Moreover, we review reported inhibitors of SET-PP2A interaction under investigation as therapeutic opportunities for the treatment of cancers.
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Affiliation(s)
- E C Dacol
- Department of Immunology, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av.Prof. Lineu Prestes, 1730, room 136, Biomedicas IV Building, São Paulo CEP 05508-000, SP, Brazil
| | - S Wang
- Laboratory of Chemical Biology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Y Chen
- Laboratory of Chemical Biology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
| | - A P Lepique
- Department of Immunology, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av.Prof. Lineu Prestes, 1730, room 136, Biomedicas IV Building, São Paulo CEP 05508-000, SP, Brazil.
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20
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MRE11 as a molecular signature and therapeutic target for cancer treatment with radiotherapy. Cancer Lett 2021; 514:1-11. [PMID: 34022282 DOI: 10.1016/j.canlet.2021.05.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/10/2021] [Accepted: 05/12/2021] [Indexed: 01/02/2023]
Abstract
MRE11, the core of the MRE11/RAD50/NBS1 complex, is one of key DNA damage response proteins. Increasing evidence suggests that its expression in cancer cells is critical to developing radioresistance; as such, MRE11 is an emerging marker for targeted radiosensitization strategies. Elevated MRE11 in tumor tissues has been associated with poor survival in patients undergoing radiotherapy, although in some cancer types, the opposite has been noted. The recent discovery of ionizing radiation-induced truncation of MRE11, which decreases its efficacy, may explain some of these paradoxical findings. The progress of research on the biological modulation of MRE11 expression is also discussed, with the potential application of small molecule or large molecule inhibitors of MRE11 for enhancing radiosensitivity. Current research has further highlighted both nuclease and non-nuclease activities of MRE11 in cancer cells treated with ionizing radiation, and differentiation between these is essential to verify the targeting effects of radiosensitizing agents. These updates clarify our understanding of how MRE11 expression may be utilized in future stratification of cancer patients for radiotherapy, and how it may be leveraged in shaping novel radiosensitization strategies.
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21
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Yu BYK, Tossounian MA, Hristov SD, Lawrence R, Arora P, Tsuchiya Y, Peak-Chew SY, Filonenko V, Oxenford S, Angell R, Gouge J, Skehel M, Gout I. Regulation of metastasis suppressor NME1 by a key metabolic cofactor coenzyme A. Redox Biol 2021; 44:101978. [PMID: 33903070 PMCID: PMC8212152 DOI: 10.1016/j.redox.2021.101978] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/28/2021] [Accepted: 04/13/2021] [Indexed: 02/08/2023] Open
Abstract
The metastasis suppressor protein NME1 is an evolutionarily conserved and multifunctional enzyme that plays an important role in suppressing the invasion and metastasis of tumour cells. The nucleoside diphosphate kinase (NDPK) activity of NME1 is well recognized in balancing the intracellular pools of nucleotide diphosphates and triphosphates to regulate cytoskeletal rearrangement and cell motility, endocytosis, intracellular trafficking, and metastasis. In addition, NME1 was found to function as a protein-histidine kinase, 3′-5′ exonuclease and geranyl/farnesyl pyrophosphate kinase. These diverse cellular functions are regulated at the level of expression, post-translational modifications, and regulatory interactions. The NDPK activity of NME1 has been shown to be inhibited in vitro and in vivo under oxidative stress, and the inhibitory effect mediated via redox-sensitive cysteine residues. In this study, affinity purification followed by mass spectrometric analysis revealed NME1 to be a major coenzyme A (CoA) binding protein in cultured cells and rat tissues. NME1 is also found covalently modified by CoA (CoAlation) at Cys109 in the CoAlome analysis of HEK293/Pank1β cells treated with the disulfide-stress inducer, diamide. Further analysis showed that recombinant NME1 is efficiently CoAlated in vitro and in cellular response to oxidising agents and metabolic stress. In vitro CoAlation of recombinant wild type NME1, but not the C109A mutant, results in the inhibition of its NDPK activity. Moreover, CoA also functions as a competitive inhibitor of the NME1 NDPK activity by binding non-covalently to the nucleotide binding site. Taken together, our data reveal metastasis suppressor protein NME1 as a novel binding partner of the key metabolic regulator CoA, which inhibits its nucleoside diphosphate kinase activity via non-covalent and covalent interactions.
NME1 is a major CoA-binding protein. CoA can bind NME1 through covalent and non-covalent interactions. NME1 CoAlation is induced by oxidative and metabolic stress in mammalian cells. CoA inhibits the NDPK activity of NME1 in vitro.
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Affiliation(s)
- Bess Yi Kun Yu
- Department of Structural and Molecular Biology, University College London, London, WC1E 6BT, United Kingdom
| | - Maria-Armineh Tossounian
- Department of Structural and Molecular Biology, University College London, London, WC1E 6BT, United Kingdom
| | - Stefan Denchev Hristov
- Department of Structural and Molecular Biology, University College London, London, WC1E 6BT, United Kingdom
| | - Ryan Lawrence
- Department of Structural and Molecular Biology, University College London, London, WC1E 6BT, United Kingdom
| | - Pallavi Arora
- Department of Structural and Molecular Biology, University College London, London, WC1E 6BT, United Kingdom
| | - Yugo Tsuchiya
- Department of Structural and Molecular Biology, University College London, London, WC1E 6BT, United Kingdom
| | - Sew Yeu Peak-Chew
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, CB2 0QH, United Kingdom
| | - Valeriy Filonenko
- Department of Cell Signaling, Institute of Molecular Biology and Genetics, Kyiv, 143, Ukraine
| | - Sally Oxenford
- School of Pharmacy, University College London, London, WC1N 1AX, United Kingdom
| | - Richard Angell
- School of Pharmacy, University College London, London, WC1N 1AX, United Kingdom
| | - Jerome Gouge
- Institute of Structural and Molecular Biology, Birkbeck College, London, WC1E 7HX, United Kingdom
| | - Mark Skehel
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, CB2 0QH, United Kingdom
| | - Ivan Gout
- Department of Structural and Molecular Biology, University College London, London, WC1E 6BT, United Kingdom; Department of Cell Signaling, Institute of Molecular Biology and Genetics, Kyiv, 143, Ukraine.
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22
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Activation of Nm23-H1 to suppress breast cancer metastasis via redox regulation. Exp Mol Med 2021; 53:346-357. [PMID: 33753879 PMCID: PMC8080780 DOI: 10.1038/s12276-021-00575-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 12/21/2020] [Accepted: 01/12/2021] [Indexed: 02/05/2023] Open
Abstract
Non-metastatic protein 23 H1 (Nm23-H1), a housekeeping enzyme, is a nucleoside diphosphate kinase-A (NDPK-A). It was the first identified metastasis suppressor protein. Nm23-H1 prolongs disease-free survival and is associated with a good prognosis in breast cancer patients. However, the molecular mechanisms underlying the role of Nm23-H1 in biological processes are still not well understood. This is a review of recent studies focusing on controlling NDPK activity based on the redox regulation of Nm23-H1, structural, and functional changes associated with the oxidation of cysteine residues, and the relationship between NDPK activity and cancer metastasis. Further understanding of the redox regulation of the NDPK function will likely provide a new perspective for developing new strategies for the activation of NDPK-A in suppressing cancer metastasis.
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Yu L, Wang X, Zhang W, Khan E, Lin C, Guo C. The multiple regulation of metastasis suppressor NM23-H1 in cancer. Life Sci 2021; 268:118995. [PMID: 33421524 DOI: 10.1016/j.lfs.2020.118995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/28/2020] [Accepted: 12/30/2020] [Indexed: 10/22/2022]
Abstract
Metastasis is one of the leading causes of mortality in cancer patients. As the firstly identified metastasis suppressor, NM23-H1 has been endowed with expectation as a potent target in metastatic cancer therapy during the past decades. However, many challenges impede its clinical use. Accumulating evidence shows that NM23-H1 has a dichotomous role in tumor metastasis as a suppressor and promoter. It has potentially attributed to its versatile biochemical characteristics such as nucleoside diphosphate kinase (NDPK) activity, histidine kinase activity (HPK), exonuclease activity, and protein scaffold, which further augment the complexity and uncertainty of its physiological function. Simultaneously, tumor cells have evolved multiple ways to regulate the expression and function of NM23-H1 during tumorigenesis and metastasis. This review summarized and discussed the regulatory mechanisms of NM23-H1 in cancer including transcriptional activation, subcellular location, enzymatic activity, and protein degradation, which significantly modulate its anti-metastatic function.
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Affiliation(s)
- Liting Yu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China
| | - Xindong Wang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China
| | - Wanheng Zhang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China; School of Engineering, China Pharmaceutical University, Nanjing, PR China
| | - Eshan Khan
- Department of Comprehensive Cancer Center, The Ohio State University, Columbus, USA
| | - Chenyu Lin
- Department of Comprehensive Cancer Center, The Ohio State University, Columbus, USA
| | - Changying Guo
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China.
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Abancens M, Bustos V, Harvey H, McBryan J, Harvey BJ. Sexual Dimorphism in Colon Cancer. Front Oncol 2020; 10:607909. [PMID: 33363037 PMCID: PMC7759153 DOI: 10.3389/fonc.2020.607909] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 11/09/2020] [Indexed: 12/12/2022] Open
Abstract
A higher incidence of colorectal cancer (CRC) is found in males compared to females. Young women (18-44 years) with CRC have a better survival outcome compared to men of the same age or compared to older women (over 50 years), indicating a global incidence of sexual dimorphism in CRC rates and survival. This suggests a protective role for the sex steroid hormone estrogen in CRC development. Key proliferative pathways in CRC tumorigenesis exhibit sexual dimorphism, which confer better survival in females through estrogen regulated genes and cell signaling. Estrogen regulates the activity of a class of Kv channels (KCNQ1:KCNE3), which control fundamental ion transport functions of the colon and epithelial mesenchymal transition through bi-directional interactions with the Wnt/β-catenin signalling pathway. Estrogen also modulates CRC proliferative responses in hypoxia via the novel membrane estrogen receptor GPER and HIF1A and VEGF signaling. Here we critically review recent clinical and molecular insights into sexual dimorphism of CRC biology modulated by the tumor microenvironment, estrogen, Wnt/β-catenin signalling, ion channels, and X-linked genes.
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Affiliation(s)
- Maria Abancens
- Department of Molecular Medicine, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin, Ireland
- Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin, Ireland
| | - Viviana Bustos
- Departamento de Acuicultura y Recursos Agroalimentarios, Programa Fitogen, Universidad de Los Lagos, Osorno, Chile
| | - Harry Harvey
- Department of Medical Oncology, Cork University Hospital, Cork, Ireland
| | - Jean McBryan
- Department of Molecular Medicine, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin, Ireland
- Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin, Ireland
| | - Brian J. Harvey
- Department of Molecular Medicine, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin, Ireland
- Centro de Estudios Cientificos CECs, Valdivia, Chile
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25
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The Impact of Drosophila Awd/NME1/2 Levels on Notch and Wg Signaling Pathways. Int J Mol Sci 2020; 21:ijms21197257. [PMID: 33019537 PMCID: PMC7582475 DOI: 10.3390/ijms21197257] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 09/18/2020] [Accepted: 09/29/2020] [Indexed: 01/09/2023] Open
Abstract
Awd, the Drosophila homologue of NME1/2 metastasis suppressors, plays key roles in many signaling pathways. Mosaic analysis of the null awdJ2A4 allele showed that loss of awd gene function blocks Notch signaling and the expression of its target genes including the Wingless (Wg/Wnt1) morphogen. We also showed that RNA interference (RNAi)-mediated awd silencing (awdi) in larval wing disc leads to chromosomal instability (CIN) and to Jun amino-terminal kinases (JNK)-mediated cell death. Here we show that this cell death is independent of p53 activity. Based on our previous finding showing that forced survival of awdi-CIN cells leads to aneuploidy without the hyperproliferative effect, we investigated the Wg expression in awdi wing disc cells. Interestingly, the Wg protein is expressed in its correct dorso-ventral domain but shows an altered cellular distribution which impairs its signaling. Further, we show that RNAi-mediated knock down of awd in wing discs does not affect Notch signaling. Thus, our analysis of the hypomorphic phenotype arising from awd downregulation uncovers a dose-dependent effect of Awd in Notch and Wg signaling.
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Adam K, Ning J, Reina J, Hunter T. NME/NM23/NDPK and Histidine Phosphorylation. Int J Mol Sci 2020; 21:E5848. [PMID: 32823988 PMCID: PMC7461546 DOI: 10.3390/ijms21165848] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/06/2020] [Accepted: 08/07/2020] [Indexed: 12/15/2022] Open
Abstract
The NME (Non-metastatic) family members, also known as NDPKs (nucleoside diphosphate kinases), were originally identified and studied for their nucleoside diphosphate kinase activities. This family of kinases is extremely well conserved through evolution, being found in prokaryotes and eukaryotes, but also diverges enough to create a range of complexity, with homologous members having distinct functions in cells. In addition to nucleoside diphosphate kinase activity, some family members are reported to possess protein-histidine kinase activity, which, because of the lability of phosphohistidine, has been difficult to study due to the experimental challenges and lack of molecular tools. However, over the past few years, new methods to investigate this unstable modification and histidine kinase activity have been reported and scientific interest in this area is growing rapidly. This review presents a global overview of our current knowledge of the NME family and histidine phosphorylation, highlighting the underappreciated protein-histidine kinase activity of NME family members, specifically in human cells. In parallel, information about the structural and functional aspects of the NME family, and the knowns and unknowns of histidine kinase involvement in cell signaling are summarized.
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Affiliation(s)
| | | | | | - Tony Hunter
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; (K.A.); (J.N.); (J.R.)
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Scott P, Anderson K, Singhania M, Cormier R. Cystic Fibrosis, CFTR, and Colorectal Cancer. Int J Mol Sci 2020; 21:E2891. [PMID: 32326161 PMCID: PMC7215855 DOI: 10.3390/ijms21082891] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 04/17/2020] [Accepted: 04/19/2020] [Indexed: 02/06/2023] Open
Abstract
Cystic fibrosis (CF), caused by biallelic inactivating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, has recently been categorized as a familial colorectal cancer (CRC) syndrome. CF patients are highly susceptible to early, aggressive colorectal tumor development. Endoscopic screening studies have revealed that by the age of forty 50% of CF patients will develop adenomas, with 25% developing aggressive advanced adenomas, some of which will have already advanced to adenocarcinomas. This enhanced risk has led to new CF colorectal cancer screening recommendations, lowering the initiation of endoscopic screening to age forty in CF patients, and to age thirty in organ transplant recipients. The enhanced risk for CRC also extends to the millions of people (more than 10 million in the US) who are heterozygous carriers of CFTR gene mutations. Further, lowered expression of CFTR is reported in sporadic CRC, where downregulation of CFTR is associated with poor survival. Mechanisms underlying the actions of CFTR as a tumor suppressor are not clearly understood. Dysregulation of Wnt/β-catenin signaling and disruption of intestinal stem cell homeostasis and intestinal barrier integrity, as well as intestinal dysbiosis, immune cell infiltration, stress responses, and intestinal inflammation have all been reported in human CF patients and in animal models. Notably, the development of new drug modalities to treat non-gastrointestinal pathologies in CF patients, especially pulmonary disease, offers hope that these drugs could be repurposed for gastrointestinal cancers.
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Affiliation(s)
| | | | | | - Robert Cormier
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA; (P.S.); (K.A.); (M.S.)
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