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53. Innate Immune Training of Human Macrophages by Cathelicidin Analogs

Author

van Dijk, Albert, Anten, Jennifer, Bakker, Anne, Evers, Noah, Hoekstra, Anna T, Chang, Jung-Chin, Scheenstra, Maaike R, Veldhuizen, Edwin J A, Netea, Mihai G, Berkers, Celia R, Haagsman, Henk P, Moleculaire afweer, Biomolecular Mass Spectrometry and Proteomics, Bijvoet Centre for Biomolecular Research, Pathobiologie, Immunologie, Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., Moleculaire afweer, Biomolecular Mass Spectrometry and Proteomics, Bijvoet Centre for Biomolecular Research, Pathobiologie, Immunologie, Veterinaire biochemie, and Sub Biomol.Mass Spectrometry & Proteom.

Subjects
Macrophages, Immunology, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], macrophage, immunomodulation, metabolomics, Immunity, Innate, Seahorse analysis, Epigenesis, Genetic, trained immunity, All institutes and research themes of the Radboud University Medical Center, Cathelicidins, cathelicidin, host defense peptide, Humans, Immunology and Allergy, Antimicrobial Cationic Peptides
Abstract

Trained innate immunity can be induced in human macrophages by microbial ligands, but it is unknown if exposure to endogenous alarmins such as cathelicidins can have similar effects. Previously, we demonstrated sustained protection against infection by the chicken cathelicidin-2 analog DCATH-2. Thus, we assessed the capacity of cathelicidins to induce trained immunity. PMA-differentiated THP-1 (dTHP1) cells were trained with cathelicidin analogs for 24 hours and restimulated after a 3-day rest period. DCATH-2 training of dTHP-1 cells amplified their proinflammatory cytokine response when restimulated with TLR2/4 agonists. Trained cells displayed a biased cellular metabolism towards mTOR-dependent aerobic glycolysis and long-chain fatty acid accumulation and augmented microbicidal activity. DCATH-2-induced trained immunity was inhibited by histone acetylase inhibitors, suggesting epigenetic regulation, and depended on caveolae/lipid raft-mediated uptake, MAPK p38 and purinergic signaling. To our knowledge, this is the first report of trained immunity by host defense peptides.

Published
2022

54. TNFR2 Costimulation Differentially Impacts Regulatory and Conventional CD4+ T-Cell Metabolism

Author

Mensink, Mark, Tran, Thi Ngoc Minh, Zaal, Esther A., Schrama, Ellen, Berkers, Celia R., Borst, Jannie, de Kivit, Sander, Biomolecular Mass Spectrometry and Proteomics, Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, Veterinaire biochemie, and Sub Biomol.Mass Spectrometry & Proteom.

Subjects
regulatory T cell, therapy, TNFR2, transcriptomics, conventional T cell, Immunology, Immunology and Allergy, metabolism
Abstract

CD4+ conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases. The opposing activities of Tconvs and Tregs depend on the stage of the immune response and their environment, with an orchestrating role for cytokine- and costimulatory receptors. Nutrient availability also impacts T-cell functionality via metabolic and biosynthetic processes that are largely unexplored. Many data argue that costimulation by Tumor Necrosis Factor Receptor 2 (TNFR2) favors support of Treg over Tconv responses and therefore TNFR2 is a key clinical target. Here, we review the pertinent literature on this topic and highlight the newly identified role of TNFR2 as a metabolic regulator for thymus-derived (t)Tregs. We present novel transcriptomic and metabolomic data that show the differential impact of TNFR2 on Tconv and tTreg gene expression and reveal distinct metabolic impact on both cell types.

Published
2022
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55. Targeting coenzyme Q10 synthesis overcomes bortezomib resistance in multiple myeloma

Author

Zaal, Esther A, de Grooth, Harm-Jan, Oudaert, Inge, Langerhorst, Pieter, Levantovsky, Sophie, van Slobbe, Gijs J J, Jansen, Jeroen W A, Menu, Eline, Wu, Wei, Berkers, Celia R, Zaal, Esther A, de Grooth, Harm-Jan, Oudaert, Inge, Langerhorst, Pieter, Levantovsky, Sophie, van Slobbe, Gijs J J, Jansen, Jeroen W A, Menu, Eline, Wu, Wei, and Berkers, Celia R

Abstract

During the development of drug resistance, multiple myeloma (MM) cells undergo changes to their metabolism. However, how these metabolic changes can be exploited to improve treatment efficacy is not known. Here we demonstrate that targeting coenzyme Q10 (CoQ) biosynthesis through the mevalonate pathway works in synergy with the proteasome inhibitor bortezomib (BTZ) in MM. We show that gene expression signatures relating to the mitochondrial tricarboxylic acid (TCA) cycle and electron transport chain (ETC) predispose to clinical BTZ resistance and poor prognosis in MM patients. Mechanistically, BTZ-resistant cells show increased activity of glutamine-driven TCA cycle and oxidative phosphorylation, together with an increased vulnerability towards ETC inhibition. Moreover, BTZ resistance is accompanied by high levels of the mitochondrial electron carrier CoQ, while the mevalonate pathway inhibitor simvastatin increases cell death and decreases CoQ levels, specifically in BTZ-resistant cells. Both in vitro and in vivo, simvastatin enhances the effect of bortezomib treatment. Our study links CoQ synthesis to drug resistance in MM and provides a novel avenue for improving BTZ responses through statin-induced inhibition of mitochondrial metabolism.

Published
2022

56. Targeting coenzyme Q10 synthesis overcomes bortezomib resistance in multiple myeloma

Author

Veterinaire biochemie, IOV MS, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, Zaal, Esther A, de Grooth, Harm-Jan, Oudaert, Inge, Langerhorst, Pieter, Levantovsky, Sophie, van Slobbe, Gijs J J, Jansen, Jeroen W A, Menu, Eline, Wu, Wei, Berkers, Celia R, Veterinaire biochemie, IOV MS, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, Zaal, Esther A, de Grooth, Harm-Jan, Oudaert, Inge, Langerhorst, Pieter, Levantovsky, Sophie, van Slobbe, Gijs J J, Jansen, Jeroen W A, Menu, Eline, Wu, Wei, and Berkers, Celia R

Published
2022

57. Innate Immune Training of Human Macrophages by Cathelicidin Analogs

Author

Moleculaire afweer, Pathobiologie, Immunologie, Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., van Dijk, Albert, Anten, Jennifer, Bakker, Anne, Evers, Noah, Hoekstra, Anna T, Chang, Jung-Chin, Scheenstra, Maaike R, Veldhuizen, Edwin J A, Netea, Mihai G, Berkers, Celia R, Haagsman, Henk P, Moleculaire afweer, Pathobiologie, Immunologie, Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., van Dijk, Albert, Anten, Jennifer, Bakker, Anne, Evers, Noah, Hoekstra, Anna T, Chang, Jung-Chin, Scheenstra, Maaike R, Veldhuizen, Edwin J A, Netea, Mihai G, Berkers, Celia R, and Haagsman, Henk P

Published
2022

58. Innate Immune Training of Human Macrophages by Cathelicidin Analogs

Author

Dijk, Albert van, Anten, Jennifer, Bakker, Anne, Evers, Noah, Hoekstra, Anna T., Chang, Jung-Chin, Netea, M.G., Berkers, Celia R., Haagsman, Henk P., Dijk, Albert van, Anten, Jennifer, Bakker, Anne, Evers, Noah, Hoekstra, Anna T., Chang, Jung-Chin, Netea, M.G., Berkers, Celia R., and Haagsman, Henk P.

Abstract

Contains fulltext : 253166.pdf (Publisher’s version ) (Open Access)

Published
2022

59. Fatty acid metabolism in aggressive B-cell lymphoma is inhibited by tetraspanin CD37

Author

Peeters, R., Cuenca Escalona, J., Zaal, Esther A., Hoekstra, Anna T., Balvert, Anouk C.G., Vidal Manrique, M., Deventer, S.J. van, Stienstra, R., Beest, M.B. ter, Berkers, Celia R., Spriel, A.B. van, Peeters, R., Cuenca Escalona, J., Zaal, Esther A., Hoekstra, Anna T., Balvert, Anouk C.G., Vidal Manrique, M., Deventer, S.J. van, Stienstra, R., Beest, M.B. ter, Berkers, Celia R., and Spriel, A.B. van

Abstract

Contains fulltext : 282219.pdf (Publisher’s version ) (Open Access)

Published
2022

60. TNFR2 Costimulation Differentially Impacts Regulatory and Conventional CD4+ T-Cell Metabolism

Author

Biomolecular Mass Spectrometry and Proteomics, Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., Mensink, Mark, Tran, Thi Ngoc Minh, Zaal, Esther A., Schrama, Ellen, Berkers, Celia R., Borst, Jannie, de Kivit, Sander, Biomolecular Mass Spectrometry and Proteomics, Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., Mensink, Mark, Tran, Thi Ngoc Minh, Zaal, Esther A., Schrama, Ellen, Berkers, Celia R., Borst, Jannie, and de Kivit, Sander

Published
2022

61. The Q-junction and the inflammatory response are critical pathological and therapeutic factors in CoQ deficiency

Author

Sub Biomol.Mass Spectrometry & Proteom., Afd Biomol.Mass Spect. and Proteomics, Veterinaire biochemie, Biomolecular Mass Spectrometry and Proteomics, González-García, Pilar, Díaz-Casado, María Elena, Hidalgo-Gutiérrez, Agustín, Jiménez-Sánchez, Laura, Bakkali, Mohammed, Barriocanal-Casado, Eliana, Escames, Germaine, Chiozzi, Riccardo Zenezini, Völlmy, Franziska, Zaal, Esther A., Berkers, Celia R., Heck, Albert J.R., López, Luis C., Sub Biomol.Mass Spectrometry & Proteom., Afd Biomol.Mass Spect. and Proteomics, Veterinaire biochemie, Biomolecular Mass Spectrometry and Proteomics, González-García, Pilar, Díaz-Casado, María Elena, Hidalgo-Gutiérrez, Agustín, Jiménez-Sánchez, Laura, Bakkali, Mohammed, Barriocanal-Casado, Eliana, Escames, Germaine, Chiozzi, Riccardo Zenezini, Völlmy, Franziska, Zaal, Esther A., Berkers, Celia R., Heck, Albert J.R., and López, Luis C.

Published
2022

62. Fatty acid metabolism in aggressive B-cell lymphoma is inhibited by tetraspanin CD37

Author

Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., Faculteit Diergeneeskunde, Biomolecular Mass Spectrometry and Proteomics, Peeters, Rens, Cuenca-Escalona, Jorge, Zaal, Esther A., Hoekstra, Anna T., Balvert, Anouk C.G., Vidal-Manrique, Marcos, Blomberg, Niek, van Deventer, Sjoerd J., Stienstra, Rinke, Jellusova, Julia, Giera, Martin, Hannibal, Luciana, Spiekerkoetter, Ute, ter Beest, Martin, Berkers, Celia R., van Spriel, Annemiek B., Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., Faculteit Diergeneeskunde, Biomolecular Mass Spectrometry and Proteomics, Peeters, Rens, Cuenca-Escalona, Jorge, Zaal, Esther A., Hoekstra, Anna T., Balvert, Anouk C.G., Vidal-Manrique, Marcos, Blomberg, Niek, van Deventer, Sjoerd J., Stienstra, Rinke, Jellusova, Julia, Giera, Martin, Hannibal, Luciana, Spiekerkoetter, Ute, ter Beest, Martin, Berkers, Celia R., and van Spriel, Annemiek B.

Published
2022

63. Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers

Author

Veterinaire biochemie, Faculteit Diergeneeskunde, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, Van Nyen, Tom, Planque, Mélanie, van Wagensveld, Lilian, Duarte, Joao A.G., Zaal, Esther A., Talebi, Ali, Rossi, Matteo, Körner, Pierre René, Rizzotto, Lara, Moens, Stijn, De Wispelaere, Wout, Baiden-Amissah, Regina E.M., Sonke, Gabe S., Horlings, Hugo M., Eelen, Guy, Berardi, Emanuele, Swinnen, Johannes V., Berkers, Celia R., Carmeliet, Peter, Lambrechts, Diether, Davidson, Ben, Agami, Reuven, Fendt, Sarah Maria, Annibali, Daniela, Amant, Frédéric, Veterinaire biochemie, Faculteit Diergeneeskunde, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, Van Nyen, Tom, Planque, Mélanie, van Wagensveld, Lilian, Duarte, Joao A.G., Zaal, Esther A., Talebi, Ali, Rossi, Matteo, Körner, Pierre René, Rizzotto, Lara, Moens, Stijn, De Wispelaere, Wout, Baiden-Amissah, Regina E.M., Sonke, Gabe S., Horlings, Hugo M., Eelen, Guy, Berardi, Emanuele, Swinnen, Johannes V., Berkers, Celia R., Carmeliet, Peter, Lambrechts, Diether, Davidson, Ben, Agami, Reuven, Fendt, Sarah Maria, Annibali, Daniela, and Amant, Frédéric

Published
2022

66. Metabolic changes underlying drug resistance in the multiple myeloma tumor microenvironment .

Author

Montoya, Mar´ıa Matamala, van Slobbe, Gijs J. J., Jung-Chin Chang, Zaal, Esther A., and Berkers, Celia R.

Subjects
MULTIDRUG resistance, MULTIPLE myeloma, TUMOR microenvironment, DRUG resistance, BONE marrow cells
Abstract

Multiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells in the bone marrow (BM). MM remains an incurable disease, with the majority of patients experiencing multiple relapses from different drugs. The MM tumor microenvironment (TME) and in particular bone-marrow stromal cells (BMSCs) play a crucial role in the development of drug resistance. Metabolic reprogramming is emerging as a hallmark of cancer that can potentially be exploited for cancer treatment. Recent studies show that metabolism is further adjusted in MM cells during the development of drug resistance. However, little is known about the role of BMSCs in inducing metabolic changes that are associated with drug resistance. In this Perspective, we summarize current knowledge concerning the metabolic reprogramming of MM, with a focus on those changes associated with drug resistance to the proteasome inhibitor Bortezomib (BTZ). In addition, we present proof-of-concept fluxomics (glucose isotope-tracing) and Seahorse data to show that co-culture of MM cells with BMSCs skews the metabolic phenotype of MM cells towards a drugresistant phenotype, with increased oxidative phosphorylation (OXPHOS), serine synthesis pathway (SSP), TCA cycle and glutathione (GSH) synthesis. Given the crucial role of BMSCs in conveying drug resistance, insights into the metabolic interaction between MM and BMSCs may ultimately aid in the identification of novel metabolic targets that can be exploited for therapy. [ABSTRACT FROM AUTHOR]

Published
2023
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67. Hyperlipidaemia elicits an atypical, T helper 1–like CD4+ T-cell response: a key role for very low-density lipoprotein.

Author

Os, Bram W van, Vos, Winnie G, Bosmans, Laura A, Tiel, Claudia M van, Lith, Sanne C, Toom, Myrthe S den, Beckers, Linda, Levels, Johannes H M, Wouw, Suzanne A E van, Zelcer, Noam, Zaal, Esther A, Berkers, Celia R, Lest, Chris H A van der, Helms, J Bernd, Weber, Christian, Atzler, Dorothee, Winther, Menno P J de, Baardman, Jeroen, and Lutgens, Esther

Subjects
T cells, HYPERLIPIDEMIA, LOW density lipoprotein receptors, LIPID rafts, DOCOSAHEXAENOIC acid
Abstract

Aims Hyperlipidemia and T cell driven inflammation are important drivers of atherosclerosis, the main underlying cause of cardiovascular disease. Here, we detailed the effects of hyperlipidemia on T cells. Methods and results In vitro, exposure of human and murine CD4+ T cells to very low-density lipoprotein (VLDL), but not to low-density lipoprotein (LDL) resulted in upregulation of Th1 associated pathways. VLDL was taken up via a CD36-dependent pathway and resulted in membrane stiffening and a reduction in lipid rafts. To further detail this response in vivo , T cells of mice lacking the LDL receptor (LDLr), which develop a strong increase in VLDL cholesterol and triglyceride levels upon high cholesterol feeding were investigated. CD4+ T cells of hyperlipidemic Ldlr -/- mice exhibited an increased expression of the C-X-C-chemokine receptor 3 (CXCR3) and produced more interferon-γ (IFN-γ). Gene set enrichment analysis identified IFN-γ-mediated signaling as the most upregulated pathway in hyperlipidemic T cells. However, the classical Th1 associated transcription factor profile with strong upregulation of Tbet and Il12rb2 was not observed. Hyperlipidemia did not affect levels of the CD4+ T cell's metabolites involved in glycolysis or other canonical metabolic pathways but enhanced amino acids levels. However, CD4+ T cells of hyperlipidemic mice showed increased cholesterol accumulation and an increased arachidonic acid (AA) to docosahexaenoic acid (DHA) ratio, which was associated with inflammatory T cell activation. Conclusions Hyperlipidemia, and especially its VLDL component induces an atypical Th1 response in CD4+ T cells. Underlying mechanisms include CD36 mediated uptake of VLDL, and an altered AA/DHA ratio. [ABSTRACT FROM AUTHOR]

Published
2023
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68. Oncogene-dependent sloppiness in mRNA translation

Author

Champagne, Julien, Pataskar, Abhijeet, Blommaert, Naomi, Nagel, Remco, Wernaart, Demi, Ramalho, Sofia, Kenski, Juliana, Bleijerveld, Onno B., Zaal, Esther A., Berkers, Celia R., Altelaar, Maarten, Peeper, Daniel S., Faller, William J., and Agami, Reuven

Published
2021
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70. Omega-3 Fatty Acids DHA and EPA Reduce Bortezomib Resistance in Multiple Myeloma Cells by Promoting Glutathione Degradation

Author

Chen, Jing, Zaal, Esther A, Berkers, Celia R, Ruijtenbeek, Rob, Garssen, Johan, Redegeld, Frank A, Afd Pharmacology, Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., dB&C FR-RMSC RMSC, Afd Chemical Biology and Drug Discovery, Pharmacology, Biomolecular Mass Spectrometry and Proteomics, Chemical Biology and Drug Discovery, Afd Pharmacology, Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., dB&C FR-RMSC RMSC, Afd Chemical Biology and Drug Discovery, Pharmacology, Biomolecular Mass Spectrometry and Proteomics, and Chemical Biology and Drug Discovery

Subjects
MAPK/ERK pathway, Docosahexaenoic Acids, QH301-705.5, Necroptosis, Antineoplastic Agents, Pharmacology, Article, Bortezomib, chemistry.chemical_compound, Multiple myeloma, Biomarkers, Tumor, Tumor Cells, Cultured, medicine, Omega-3 fatty acids, Humans, Biology (General), Medicine(all), drug resistance, omega-3 fatty acids, Chemistry, multiple myeloma, bortezomib, DHA, EPA, transcriptome, metabolome, General Medicine, Glutathione, medicine.disease, Eicosapentaenoic acid, Gene Expression Regulation, Neoplastic, Eicosapentaenoic Acid, Docosahexaenoic acid, Drug resistance, Proteasome inhibitor, Metabolome, Tran-scriptome, Signal Transduction, medicine.drug
Abstract

Multiple myeloma (MM) is a hematological malignancy that exhibits aberrantly high levels of proteasome activity. While treatment with the proteasome inhibitor bortezomib substantially increases overall survival of MM patients, acquired drug resistance remains the main challenge for MM treatment. Using a combination treatment of docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) and bortezomib, it was demonstrated previously that pretreatment with DHA/EPA significantly increased bortezomib chemosensitivity in MM cells. In the current study, both transcriptome and metabolome analysis were performed to comprehensively evaluate the underlying mechanism. It was demonstrated that pretreating MM cells with DHA/EPA before bortezomib potently decreased the cellular glutathione (GSH) level and altered the expression of the related metabolites and key enzymes in GSH metabolism, whereas simultaneous treatment only showed minor effects on these factors, thereby suggesting the critical role of GSH degradation in overcoming bortezomib resistance in MM cells. Moreover, RNA-seq results revealed that the nuclear factor erythroid 2-related factor 2 (NRF2)-activating transcription factor 3/4 (ATF3/4)-ChaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1) signaling pathway may be implicated as the central player in the GSH degradation. Pathways of necroptosis, ferroptosis, p53, NRF2, ATF4, WNT, MAPK, NF-κB, EGFR, and ERK may be connected to the tumor suppressive effect caused by pretreatment of DHA/EPA prior to bortezomib. Collectively, this work implicates GSH degradation as a potential therapeutic target in MM and provides novel mechanistic insights into its significant role in combating bortezomib resistance.

Published
2021

72. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells

Author

Maddocks, Oliver D.K., Berkers, Celia R., Mason, Susan M., Zheng, Liang, Blyth, Karen, Gottlieb, Eyal, and Vousden, Karen H.

Subjects
Physiological aspects, Health aspects, Oxidative stress -- Physiological aspects -- Health aspects, Cancer cells -- Physiological aspects -- Health aspects, Tumor suppressor genes -- Physiological aspects -- Health aspects, Serine -- Physiological aspects -- Health aspects
Abstract

Cancer cells acquire distinct metabolic adaptations to survive stress associated with tumour growth and to satisfy the anabolic demands of proliferation. The tumour suppressor protein p53 (also known as TP53) [...]

Published
2013
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73. Molecular basis of bortezomib resistance: proteasome subunit β5 (PSMB5) gene mutation and overexpression of PSMB5 protein

Author

Oerlemans, Ruud, Franke, Niels E., Assaraf, Yehuda G., Cloos, Jacqueline, van Zantwijk, Ina, Berkers, Celia R., Scheffer, George L., Debipersad, Kabir, Vojtekova, Katharina, Lemos, Clara, van der Heijden, Joost W., Ylstra, Bauke, Peters, Godefridus J., Kaspers, Gertjan L., Dijkmans, Ben A.C., Scheper, Rik J., and Jansen, Gerrit

Published
2008
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75. A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer

Author

Jin, Haojie, Wang, Siying, Zaal, Esther A, Wang, Cun, Wu, Haiqiu, Bosma, Astrid, Jochems, Fleur, Isima, Nikita, Jin, Guangzhi, Lieftink, Cor, Beijersbergen, Roderick, Berkers, Celia R, Qin, Wenxin, Bernards, Rene, Sub Biomol.Mass Spectrometry & Proteom., Veterinaire biochemie, dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, Al het onderzoek van de faculteit Diergeneeskunde, Sub Biomol.Mass Spectrometry & Proteom., Veterinaire biochemie, dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, and Al het onderzoek van de faculteit Diergeneeskunde

Subjects
0301 basic medicine, glutaminolysis, Glutamine, Benzeneacetamides, Apoptosis, Mice, 0302 clinical medicine, Biology (General), Cancer Biology, chemistry.chemical_classification, Glutaminase, General Neuroscience, Liver Neoplasms, Drug Synergism, General Medicine, hepatocellular carcinoma, 030220 oncology & carcinogenesis, Medicine, Research Article, Human, Amino Acid Transport System ASC, QH301-705.5, Science, Antineoplastic Agents, General Biochemistry, Genetics and Molecular Biology, Minor Histocompatibility Antigens, 03 medical and health sciences, In vivo, Cell Line, Tumor, Thiadiazoles, Animals, Humans, CB-839, glutamine addiction, Reactive oxygen species, Glutaminolysis, General Immunology and Microbiology, Transporter, Xenograft Model Antitumor Assays, 030104 developmental biology, chemistry, Cancer cell, Cancer research, Carrier Proteins, Reactive Oxygen Species
Abstract

The dependency of cancer cells on glutamine may be exploited therapeutically as a new strategy for treating cancers that lack druggable driver genes. Here we found that human liver cancer was dependent on extracellular glutamine. However, targeting glutamine addiction using the glutaminase inhibitor CB-839 as monotherapy had a very limited anticancer effect, even against the most glutamine addicted human liver cancer cells. Using a chemical library, we identified V-9302, a novel inhibitor of glutamine transporter ASCT2, as sensitizing glutamine dependent (GD) cells to CB-839 treatment. Mechanically, a combination of CB-839 and V-9302 depleted glutathione and induced reactive oxygen species (ROS), resulting in apoptosis of GD cells. Moreover, this combination also showed tumor inhibition in HCC xenograft mouse models in vivo. Our findings indicate that dual inhibition of glutamine metabolism by targeting both glutaminase and glutamine transporter ASCT2 represents a potential novel treatment strategy for glutamine addicted liver cancers.

Published
2020

76. Oncogene-dependent sloppiness in mRNA translation

Author

Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., dB&C FR-RMSC RMSC, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Champagne, Julien, Pataskar, Abhijeet, Blommaert, Naomi, Nagel, Remco, Wernaart, Demi, Ramalho, Sofia, Kenski, Juliana, Bleijerveld, Onno B, Zaal, Esther A, Berkers, Celia R, Altelaar, Maarten, Peeper, Daniel S, Faller, William J, Agami, Reuven, Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., dB&C FR-RMSC RMSC, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Champagne, Julien, Pataskar, Abhijeet, Blommaert, Naomi, Nagel, Remco, Wernaart, Demi, Ramalho, Sofia, Kenski, Juliana, Bleijerveld, Onno B, Zaal, Esther A, Berkers, Celia R, Altelaar, Maarten, Peeper, Daniel S, Faller, William J, and Agami, Reuven

Published
2021

77. Omega-3 Fatty Acids DHA and EPA Reduce Bortezomib Resistance in Multiple Myeloma Cells by Promoting Glutathione Degradation

Author

Afd Pharmacology, Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., dB&C FR-RMSC RMSC, Afd Chemical Biology and Drug Discovery, Pharmacology, Biomolecular Mass Spectrometry and Proteomics, Chemical Biology and Drug Discovery, Chen, Jing, Zaal, Esther A, Berkers, Celia R, Ruijtenbeek, Rob, Garssen, Johan, Redegeld, Frank A, Afd Pharmacology, Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., dB&C FR-RMSC RMSC, Afd Chemical Biology and Drug Discovery, Pharmacology, Biomolecular Mass Spectrometry and Proteomics, Chemical Biology and Drug Discovery, Chen, Jing, Zaal, Esther A, Berkers, Celia R, Ruijtenbeek, Rob, Garssen, Johan, and Redegeld, Frank A

Published
2021

78. Cysteamine–bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis

Author

Afd Pharmacology, Afd Biomol.Mass Spect. and Proteomics, Veterinaire biochemie, Dep Scheikunde, Faculteit Diergeneeskunde, Sub Biomol.Mass Spectrometry & Proteom., dB&C FR-RMSC RMSC, Pharmacology, Biomolecular Mass Spectrometry and Proteomics, Jamalpoor, Amer, van Gelder, Charlotte A.G.H., Yousef Yengej, Fjodor A., Zaal, Esther A., Berlingerio, Sante P., Veys, Koenraad R., Pou Casellas, Carla, Voskuil, Koen, Essa, Khaled, Ammerlaan, Carola M.E., Rega, Laura Rita, van der Welle, Reini E.N., Lilien, Marc R., Rookmaaker, Maarten B., Clevers, Hans, Klumperman, Judith, Levtchenko, Elena, Berkers, Celia R., Verhaar, Marianne C., Altelaar, Maarten, Masereeuw, Rosalinde, Janssen, Manoe J., Afd Pharmacology, Afd Biomol.Mass Spect. and Proteomics, Veterinaire biochemie, Dep Scheikunde, Faculteit Diergeneeskunde, Sub Biomol.Mass Spectrometry & Proteom., dB&C FR-RMSC RMSC, Pharmacology, Biomolecular Mass Spectrometry and Proteomics, Jamalpoor, Amer, van Gelder, Charlotte A.G.H., Yousef Yengej, Fjodor A., Zaal, Esther A., Berlingerio, Sante P., Veys, Koenraad R., Pou Casellas, Carla, Voskuil, Koen, Essa, Khaled, Ammerlaan, Carola M.E., Rega, Laura Rita, van der Welle, Reini E.N., Lilien, Marc R., Rookmaaker, Maarten B., Clevers, Hans, Klumperman, Judith, Levtchenko, Elena, Berkers, Celia R., Verhaar, Marianne C., Altelaar, Maarten, Masereeuw, Rosalinde, and Janssen, Manoe J.

Published
2021

79. Anti-tumour immunity induces aberrant peptide presentation in melanoma

Author

Dep Scheikunde, Veterinaire biochemie, Sub Biomol.Mass Spect. and Proteomics, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, Bartok, Osnat, Pataskar, Abhijeet, Nagel, Remco, Laos, Maarja, Goldfarb, Eden, Hayoun, Deborah, Levy, Ronen, Körner, Pierre-Rene, Kreuger, Inger Z M, Champagne, Julien, Zaal, Esther A, Bleijerveld, Onno B, Huang, Xinyao, Kenski, Juliana, Wargo, Jennifer, Brandis, Alexander, Levin, Yishai, Mizrahi, Orel, Alon, Michal, Lebon, Sacha, Yang, Weiwen, Nielsen, Morten M, Stern-Ginossar, Noam, Altelaar, Maarten, Berkers, Celia R, Geiger, Tamar, Peeper, Daniel S, Olweus, Johanna, Samuels, Yardena, Agami, Reuven, Dep Scheikunde, Veterinaire biochemie, Sub Biomol.Mass Spect. and Proteomics, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, Bartok, Osnat, Pataskar, Abhijeet, Nagel, Remco, Laos, Maarja, Goldfarb, Eden, Hayoun, Deborah, Levy, Ronen, Körner, Pierre-Rene, Kreuger, Inger Z M, Champagne, Julien, Zaal, Esther A, Bleijerveld, Onno B, Huang, Xinyao, Kenski, Juliana, Wargo, Jennifer, Brandis, Alexander, Levin, Yishai, Mizrahi, Orel, Alon, Michal, Lebon, Sacha, Yang, Weiwen, Nielsen, Morten M, Stern-Ginossar, Noam, Altelaar, Maarten, Berkers, Celia R, Geiger, Tamar, Peeper, Daniel S, Olweus, Johanna, Samuels, Yardena, and Agami, Reuven

Published
2021

80. Treatment with HIV-protease inhibitor nelfinavir identifies membrane lipid composition and fluidity as a therapeutic target in advanced multiple myeloma

Author

Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, Besse, Lenka, Besse, Andrej, Stolze, Sara C., Sobh, Amin, Zaal, Esther A., Ham, Alwin J.Van Der, Ruiz, Mario, Phuyal, Santosh, Buchler, Lorina, Sathianathan, Marc, Florea, Bogdan I., Boren, Jan, Hlman, Marcus Sta, Huber, Julia, Bolomsky, Arnold, Ludwig, Heinz, Hannich, J. Thomas, Loguinov, Alex, Everts, Bart, Berkers, Celia R., Pilon, Marc, Farhan, Hesso, Vulpe, Christopher D., Overkleeft, Herman S., Driessen, Christoph, Veterinaire biochemie, Sub Biomol.Mass Spectrometry & Proteom., dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, Besse, Lenka, Besse, Andrej, Stolze, Sara C., Sobh, Amin, Zaal, Esther A., Ham, Alwin J.Van Der, Ruiz, Mario, Phuyal, Santosh, Buchler, Lorina, Sathianathan, Marc, Florea, Bogdan I., Boren, Jan, Hlman, Marcus Sta, Huber, Julia, Bolomsky, Arnold, Ludwig, Heinz, Hannich, J. Thomas, Loguinov, Alex, Everts, Bart, Berkers, Celia R., Pilon, Marc, Farhan, Hesso, Vulpe, Christopher D., Overkleeft, Herman S., and Driessen, Christoph

Published
2021

81. Immunotherapeutic potential for ceramide-based activators of iNKT cells

Author

Berkers, Celia R. and Ovaa, Huib

Subjects
Communicable diseases -- Drug therapy, Cancer -- Drug therapy, Autoimmune diseases -- Drug therapy, T cells, Glycolipids, Immunotherapy, Biological sciences, Chemistry, Pharmaceuticals and cosmetics industries
Abstract

Invariant natural killer T (iNKT) cells are a subpopulation of T cells that are reactive with glycolipids that are bound by CD1d antigen-presenting molecules. [alpha]-Galactosylceramide ([alpha]-GalCer) is a synthetic glycolipid that is a potential treatment for several autoimmune diseases, infectious diseases and cancer. Its therapeutic effect can be traced back to its ability to bind CD1d and activate iNKT cells, which results in the production of T helper 1 (Th1) and Th2 cytokines. However, the effectiveness of [alpha]-GalCer therapy is limited by the opposing actions of Th1 and Th2 cytokines. The [alpha]-GalCer analogs OCH and the recently designed and synthesized C-glycosidic [alpha]-GalCer selectively activate one of two types of cytokine profiles, possibly because either reduced or enhanced overall stability of the CD1d--glycolipid--T-cell-receptor complex leads to a higher potency in vivo, compared with the parent compound. These discoveries boost the potential of glycolipid-based therapies.

Published
2005

83. TNFR2 Costimulation Differentially Impacts Regulatory and Conventional CD4+ T-Cell Metabolism.

Author

Mensink, Mark, Tran, Thi Ngoc Minh, Zaal, Esther A., Schrama, Ellen, Berkers, Celia R., Borst, Jannie, and de Kivit, Sander

Subjects
REGULATORY T cells, TUMOR necrosis factor receptors, T cells, METABOLISM, IMMUNE response
Abstract

CD4+ conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases. The opposing activities of Tconvs and Tregs depend on the stage of the immune response and their environment, with an orchestrating role for cytokine- and costimulatory receptors. Nutrient availability also impacts T-cell functionality via metabolic and biosynthetic processes that are largely unexplored. Many data argue that costimulation by Tumor Necrosis Factor Receptor 2 (TNFR2) favors support of Treg over Tconv responses and therefore TNFR2 is a key clinical target. Here, we review the pertinent literature on this topic and highlight the newly identified role of TNFR2 as a metabolic regulator for thymus-derived (t)Tregs. We present novel transcriptomic and metabolomic data that show the differential impact of TNFR2 on Tconv and tTreg gene expression and reveal distinct metabolic impact on both cell types. [ABSTRACT FROM AUTHOR]

Published
2022
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84. A Fluorescent Broad-Spectrum Proteasome Inhibitor for Labeling Proteasomes In Vitro and In Vivo

Author

Verdoes, Martijn, Florea, Bogdan I., Menendez-Benito, Victoria, Maynard, Christa J., Witte, Martin D., van der Linden, Wouter A., van den Nieuwendijk, Adrianus M.C.H., Hofmann, Tanja, Berkers, Celia R., van Leeuwen, Fijs W.B., Groothuis, Tom A., Leeuwenburgh, Michiel A., Ovaa, Huib, Neefjes, Jacques J., Filippov, Dmitri V., van der Marel, Gijs A., Dantuma, Nico P., and Overkleeft, Herman S.

Published
2006
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87. Anti-tumour immunity induces aberrant peptide presentation in melanoma

Author

Bartok, Osnat, primary, Pataskar, Abhijeet, additional, Nagel, Remco, additional, Laos, Maarja, additional, Goldfarb, Eden, additional, Hayoun, Deborah, additional, Levy, Ronen, additional, Körner, Pierre-Rene, additional, Kreuger, Inger Z. M., additional, Champagne, Julien, additional, Zaal, Esther A., additional, Bleijerveld, Onno B., additional, Huang, Xinyao, additional, Kenski, Juliana, additional, Wargo, Jennifer, additional, Brandis, Alexander, additional, Levin, Yishai, additional, Mizrahi, Orel, additional, Alon, Michal, additional, Lebon, Sacha, additional, Yang, Weiwen, additional, Nielsen, Morten M., additional, Stern-Ginossar, Noam, additional, Altelaar, Maarten, additional, Berkers, Celia R., additional, Geiger, Tamar, additional, Peeper, Daniel S., additional, Olweus, Johanna, additional, Samuels, Yardena, additional, and Agami, Reuven, additional

Published
2020
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88. Nelfinavir Overcomes Proteasome Inhibitor Resistance in Multiple Myeloma By Modulating Membrane Lipid Bilayer Composition and Fluidity

Author

Besse, Andrej, primary, Besse, Lenka, additional, Stolze, Sara C., additional, Sobh, Amin, additional, Zaal, Esther A., additional, van der Ham, Alwin J, additional, Ruiz, Mario, additional, Phuyal, Santosh, additional, Büchler, Lorina, additional, Sathianathan, Marc, additional, Florea, Bogdan I., additional, Borén, Jan, additional, Ståhlman, Marcus, additional, Loguinov, Alex, additional, Everts, Bart, additional, Berkers, Celia R., additional, Pilon, Marc, additional, Farhan, Hesso, additional, Vulpe, Chris D., additional, Overkleeft, Herman S., additional, and Driessen, Christoph, additional

Published
2020
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89. Author response: A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer

Author

Jin, Haojie, primary, Wang, Siying, additional, Zaal, Esther A, additional, Wang, Cun, additional, Wu, Haiqiu, additional, Bosma, Astrid, additional, Jochems, Fleur, additional, Isima, Nikita, additional, Jin, Guangzhi, additional, Lieftink, Cor, additional, Beijersbergen, Roderick, additional, Berkers, Celia R, additional, Qin, Wenxin, additional, and Bernards, Rene, additional

Published
2020
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90. The lysosomal V-ATPase B1 subunit in proximal tubule is linked to nephropathic cystinosis

Author

Jamalpoor, Amer, primary, van Eerde, Albertien M, additional, Lilien, Marc R, additional, van Gelder, Charlotte AGH, additional, Zaal, Esther A, additional, Valentijn, Floris A, additional, Broekhuizen, Roel, additional, Zielhuis, Eva, additional, Egido, Julia E, additional, Altelaar, Maarten, additional, Berkers, Celia R, additional, Masereeuw, Rosalinde, additional, and Janssen, Manoe J, additional

Published
2020
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91. A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer

Author

Sub Biomol.Mass Spectrometry & Proteom., Veterinaire biochemie, dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, Al het onderzoek van de faculteit Diergeneeskunde, Jin, Haojie, Wang, Siying, Zaal, Esther A, Wang, Cun, Wu, Haiqiu, Bosma, Astrid, Jochems, Fleur, Isima, Nikita, Jin, Guangzhi, Lieftink, Cor, Beijersbergen, Roderick, Berkers, Celia R, Qin, Wenxin, Bernards, Rene, Sub Biomol.Mass Spectrometry & Proteom., Veterinaire biochemie, dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, Al het onderzoek van de faculteit Diergeneeskunde, Jin, Haojie, Wang, Siying, Zaal, Esther A, Wang, Cun, Wu, Haiqiu, Bosma, Astrid, Jochems, Fleur, Isima, Nikita, Jin, Guangzhi, Lieftink, Cor, Beijersbergen, Roderick, Berkers, Celia R, Qin, Wenxin, and Bernards, Rene

Published
2020

92. Stable human regulatory T cells switch to glycolysis following TNF receptor 2 costimulation

Author

Sub Immunopharmacology, Sub Biomol.Mass Spectrometry & Proteom., Veterinaire biochemie, dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, de Kivit, Sander, Mensink, Mark, Hoekstra, Anna T, Berlin, Ilana, Derks, Rico J E, Both, Demi, Aslam, Muhammad A, Amsen, Derk, Berkers, Celia R, Borst, Jannie, Sub Immunopharmacology, Sub Biomol.Mass Spectrometry & Proteom., Veterinaire biochemie, dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, de Kivit, Sander, Mensink, Mark, Hoekstra, Anna T, Berlin, Ilana, Derks, Rico J E, Both, Demi, Aslam, Muhammad A, Amsen, Derk, Berkers, Celia R, and Borst, Jannie

Published
2020

93. Cysteamine-bicalutamide combination treatment restores alpha-ketoglutarate and corrects proximal tubule phenotype in cystinosis

Author

Jamalpoor, Amer, primary, van Gelder, Charlotte AGH, additional, Yousef Yengej, Fjodor A, additional, Zaal, Esther A, additional, Berlingerio, Sante Princiero, additional, Veys, Koenraad R, additional, Casellas, Carla Pou, additional, Voskuil, Koen, additional, Essa, Khaled, additional, Ammerlaan, Carola ME, additional, Rega, Laura Rita, additional, van der Welle, Reini, additional, Lilien, Marc R, additional, Rookmaaker, Maarten B, additional, Clevers, Hans, additional, Klumperman, Judith, additional, Levtchenko, Elena, additional, Berkers, Celia R, additional, Verhaar, Marianne C, additional, Altelaar, Maarten, additional, Masereeuw, Rosalinde, additional, and Janssen, Manoe J, additional

Published
2020
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94. The Influence of Metabolism on Drug Response in Cancer

Author

Zaal, Esther A, Berkers, Celia R, Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., and dB&C FR-RMSC RMSC

Subjects
0301 basic medicine, Cancer Research, medicine.medical_treatment, cancer metabolism, cisplatin, Review, Drug resistance, lcsh:RC254-282, 03 medical and health sciences, Breast cancer, breast cancer, medicine, melanoma, Cisplatin, Chemotherapy, drug resistance, Bortezomib, business.industry, Melanoma, bortezomib, Cancer, BRAF inhibitors, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, multiple myeloma, 030104 developmental biology, Oncology, Cancer cell, Cancer research, business, medicine.drug
Abstract

Resistance to therapeutic agents, either intrinsic or acquired, is currently a major problem in the treatment of cancers and occurs in virtually every type of anti-cancer therapy. Therefore, understanding how resistance can be prevented, targeted and predicted becomes increasingly important to improve cancer therapy. In the last decade, it has become apparent that alterations in cellular metabolism are a hallmark of cancer cells and that a rewired metabolism is essential for rapid tumor growth and proliferation. Recently, metabolic alterations have been shown to play a role in the sensitivity of cancer cells to widely-used first-line chemotherapeutics. This suggests that metabolic pathways are important mediators of resistance toward anticancer agents. In this review, we highlight the metabolic alterations associated with resistance toward different anticancer agents and discuss how metabolism may be exploited to overcome drug resistance to classical chemotherapy.

Published
2018
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95. SLC 1A3 contributes to L‐asparaginase resistance in solid tumors

Author

Sun, Jianhui, primary, Nagel, Remco, additional, Zaal, Esther A, additional, Ugalde, Alejandro Piñeiro, additional, Han, Ruiqi, additional, Proost, Natalie, additional, Song, Ji‐Ying, additional, Pataskar, Abhijeet, additional, Burylo, Artur, additional, Fu, Haigen, additional, Poelarends, Gerrit J, additional, van de Ven, Marieke, additional, van Tellingen, Olaf, additional, Berkers, Celia R, additional, and Agami, Reuven, additional

Published
2019
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96. SLC1A3 contributes to L-asparaginase resistance in solid tumors

Author

Sub Biomol.Mass Spectrometry & Proteom., LS Veterinaire biochemie, dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, Dep Biochemie en Celbiologie, Sun, Jianhui, Nagel, Remco, Zaal, Esther A., Ugalde, Alejandro Piñeiro, Han, Ruiqi, Proost, Natalie, Song, Ji Ying, Pataskar, Abhijeet, Burylo, Artur, Fu, Haigen, Poelarends, Gerrit J., van de Ven, Marieke, van Tellingen, Olaf, Berkers, Celia R., Agami, Reuven, Sub Biomol.Mass Spectrometry & Proteom., LS Veterinaire biochemie, dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, Dep Biochemie en Celbiologie, Sun, Jianhui, Nagel, Remco, Zaal, Esther A., Ugalde, Alejandro Piñeiro, Han, Ruiqi, Proost, Natalie, Song, Ji Ying, Pataskar, Abhijeet, Burylo, Artur, Fu, Haigen, Poelarends, Gerrit J., van de Ven, Marieke, van Tellingen, Olaf, Berkers, Celia R., and Agami, Reuven

Published
2019

97. A fragment-like approach to PYCR1 inhibition

Author

Sub Biomol.Mass Spectrometry & Proteom., LS Veterinaire biochemie, dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, Dep Biochemie en Celbiologie, Milne, Kirsty, Sun, Jianhui, Zaal, Esther A., Mowat, Jenna, Celie, Patrick H.N., Fish, Alexander, Berkers, Celia R., Forlani, Giuseppe, Loayza-Puch, Fabricio, Jamieson, Craig, Agami, Reuven, Sub Biomol.Mass Spectrometry & Proteom., LS Veterinaire biochemie, dB&C FR-RMSC RMSC, Biomolecular Mass Spectrometry and Proteomics, Dep Biochemie en Celbiologie, Milne, Kirsty, Sun, Jianhui, Zaal, Esther A., Mowat, Jenna, Celie, Patrick H.N., Fish, Alexander, Berkers, Celia R., Forlani, Giuseppe, Loayza-Puch, Fabricio, Jamieson, Craig, and Agami, Reuven

Published
2019

98. Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion

Author

Afd Pharmacology, Afd Chemical Biology and Drug Discovery, Sub Biomol.Mass Spectrometry & Proteom., LS Veterinaire biochemie, dB&C FR-RMSC RMSC, Pharmacology, Chemical Biology and Drug Discovery, Biomolecular Mass Spectrometry and Proteomics, Jansen, Jitske, Jansen, Katja, Neven, Ellen, Poesen, Ruben, Othman, Amr, van Mil, Alain, Sluijter, Joost, Sastre Torano, Javier, Zaal, Esther A, Berkers, Celia R, Esser, Diederik, Wichers, Harry J, van Ede, Karin, van Duursen, Majorie, Burtey, Stéphane, Verhaar, Marianne C, Meijers, Björn, Masereeuw, Rosalinde, Afd Pharmacology, Afd Chemical Biology and Drug Discovery, Sub Biomol.Mass Spectrometry & Proteom., LS Veterinaire biochemie, dB&C FR-RMSC RMSC, Pharmacology, Chemical Biology and Drug Discovery, Biomolecular Mass Spectrometry and Proteomics, Jansen, Jitske, Jansen, Katja, Neven, Ellen, Poesen, Ruben, Othman, Amr, van Mil, Alain, Sluijter, Joost, Sastre Torano, Javier, Zaal, Esther A, Berkers, Celia R, Esser, Diederik, Wichers, Harry J, van Ede, Karin, van Duursen, Majorie, Burtey, Stéphane, Verhaar, Marianne C, Meijers, Björn, and Masereeuw, Rosalinde

Published
2019

99. Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion

Author

Researchbureau DHL, Experimentele Afd. Cardiologie 2, Onderzoek Cardiovasculair Reg. Med., Circulatory Health, Regenerative Medicine and Stem Cells, CDL Rode cel, Nefro Vasculaire Geneeskunde, Jansen, Jitske, Jansen, Katja, Neven, Ellen, Poesen, Ruben, Othman, Amr, van Mil, Alain, Sluijter, Joost, Torano, Javier Sastre, Zaal, Esther A., Berkers, Celia R., Esser, Diederik, Wichers, Harry J., van Ede, Karin, van Duursen, Majorie, Burtey, Stéphane, Verhaar, Marianne C., Meijers, Björn, Masereeuw, Rosalinde, Researchbureau DHL, Experimentele Afd. Cardiologie 2, Onderzoek Cardiovasculair Reg. Med., Circulatory Health, Regenerative Medicine and Stem Cells, CDL Rode cel, Nefro Vasculaire Geneeskunde, Jansen, Jitske, Jansen, Katja, Neven, Ellen, Poesen, Ruben, Othman, Amr, van Mil, Alain, Sluijter, Joost, Torano, Javier Sastre, Zaal, Esther A., Berkers, Celia R., Esser, Diederik, Wichers, Harry J., van Ede, Karin, van Duursen, Majorie, Burtey, Stéphane, Verhaar, Marianne C., Meijers, Björn, and Masereeuw, Rosalinde

Published
2019

100. Proteomic and Metabolomic Analyses of Vanishing White Matter Mouse Astrocytes Reveal Deregulation of ER Functions

Author

Wisse, Lisanne E., Penning, Renske, Zaal, Esther A., van Berkel, Carola G M, ter Braak, Timo J., Polder, Emiel, Kenney, Justin W., Proud, Christopher G, Berkers, Celia R., Altelaar, Maarten A.F., Speijer, Dave, van der Knaap, Marjo S, Abbink, Truus E.M., Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, Pediatric surgery, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Reproduction & Development (AR&D), Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Medical Biochemistry, and Other departments

Subjects
0301 basic medicine, Pentose phosphate pathway, Vanishing white matter, SILAC, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, Stable isotope labeling by amino acids in cell culture, medicine, Protein biosynthesis, Metabolomics, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Secretory pathway, Original Research, biology, Chemistry, Endoplasmic reticulum, astrocytes, Translation (biology), metabolomics, Cell biology, endoplasmic reticulum, 030104 developmental biology, medicine.anatomical_structure, vanishing white matter, Astrocytes, AHA, eIF2B, biology.protein, Astrocyte, Neuroscience
Abstract

Vanishing white matter (VWM) is a leukodystrophy with predominantly early-childhood onset. Affected children display various neurological signs, including ataxia and spasticity, and die early. VWM patients have bi-allelic mutations in any of the five genes encoding the subunits of the eukaryotic translation factor 2B (eIF2B). eIF2B regulates protein synthesis rates under basal and cellular stress conditions. The underlying molecular mechanism of how mutations in eIF2B result in VWM is unknown. Previous studies suggest that brain white matter astrocytes are primarily affected in VWM. We hypothesized that the translation rate of certain astrocytic mRNAs is affected by the mutations, resulting in astrocytic dysfunction. Here we subjected primary astrocyte cultures of wild type (wt) and VWM (2b5ho) mice to pulsed labeling proteomics based on stable isotope labeling with amino acids in cell culture (SILAC) with an L-azidohomoalanine (AHA) pulse to select newly synthesized proteins. AHA was incorporated into newly synthesized proteins in wt and 2b5ho astrocytes with similar efficiency, without affecting cell viability. We quantified proteins synthesized in astrocytes of wt and 2b5ho mice. This proteomic profiling identified a total of 80 proteins that were regulated by the eIF2B mutation.We confirmed increased expression of PROS1 in 2b5ho astrocytes and brain. A DAVID enrichment analysis showed that approximately 50% of the eIF2B-regulated proteins used the secretory pathway. A small-scale metabolic screen further highlighted a significant change in the metabolite 6-phospho-gluconate, indicative of an altered flux through the pentose phosphate pathway (PPP). Some of the proteins migrating through the secretory pathway undergo oxidative folding reactions in the endoplasmic reticulum (ER), which produces reactive oxygen species (ROS). The PPP produces NADPH to remove ROS. The proteomic and metabolomics data together suggest a deregulation of ER function in 2b5ho mouse astrocytes.

Published
2017
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