Depletion of pyruvate kinase (PK) activity causes glycolytic intermediate imbalances and reveals a PK-TXNIP regulatory axis
Objective: Cancer cells convert more glucose into lactate than healthy cells, what contributes to their growth advantage. Pyruvate kinase (PK) is a key rate limiting enzyme in this process, what makes it a promising potential therapeutic target. However, currently it is still unclear what consequenc...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877823000820 |
| _version_ | 1827900131214622720 |
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| author | Anna Nieborak Saulius Lukauskas Jordi Capellades Patricia Heyn Gabriela Silva Santos Karsten Motzler Anja Zeigerer Romina Bester Ulrike Protzer Florian Schelter Mirko Wagner Thomas Carell Alexander Hruscha Bettina Schmid Oscar Yanes Robert Schneider |
| author_facet | Anna Nieborak Saulius Lukauskas Jordi Capellades Patricia Heyn Gabriela Silva Santos Karsten Motzler Anja Zeigerer Romina Bester Ulrike Protzer Florian Schelter Mirko Wagner Thomas Carell Alexander Hruscha Bettina Schmid Oscar Yanes Robert Schneider |
| author_sort | Anna Nieborak |
| collection | DOAJ |
| description | Objective: Cancer cells convert more glucose into lactate than healthy cells, what contributes to their growth advantage. Pyruvate kinase (PK) is a key rate limiting enzyme in this process, what makes it a promising potential therapeutic target. However, currently it is still unclear what consequences the inhibition of PK has on cellular processes. Here, we systematically investigate the consequences of PK depletion for gene expression, histone modifications and metabolism. Methods: Epigenetic, transcriptional and metabolic targets were analysed in different cellular and animal models with stable knockdown or knockout of PK. Results: Depleting PK activity reduces the glycolytic flux and causes accumulation of glucose-6-phosphate (G6P). Such metabolic perturbation results in stimulation of the activity of a heterodimeric pair of transcription factors MondoA and MLX but not in a major reprogramming of the global H3K9ac and H3K4me3 histone modification landscape. The MondoA:MLX heterodimer upregulates expression of thioredoxin-interacting protein (TXNIP) – a tumour suppressor with multifaceted anticancer activity. This effect of TXNIP upregulation extends beyond immortalised cancer cell lines and is applicable to multiple cellular and animal models. Conclusions: Our work shows that actions of often pro-tumorigenic PK and anti-tumorigenic TXNIP are tightly linked via a glycolytic intermediate. We suggest that PK depletion stimulates the activity of MondoA:MLX transcription factor heterodimers and subsequently, increases cellular TXNIP levels. TXNIP-mediated inhibition of thioredoxin (TXN) can reduce the ability of cells to scavenge reactive oxygen species (ROS) leading to the oxidative damage of cellular structures including DNA. These findings highlight an important regulatory axis affecting tumour suppression mechanisms and provide an attractive opportunity for combination cancer therapies targeting glycolytic activity and ROS-generating pathways. |
| first_indexed | 2024-03-12T23:26:51Z |
| format | Article |
| id | doaj.art-1cdb8cc6c3104464995700a9b14eb2eb |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-03-12T23:26:51Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-1cdb8cc6c3104464995700a9b14eb2eb2023-07-16T04:18:28ZengElsevierMolecular Metabolism2212-87782023-08-0174101748Depletion of pyruvate kinase (PK) activity causes glycolytic intermediate imbalances and reveals a PK-TXNIP regulatory axisAnna Nieborak0Saulius Lukauskas1Jordi Capellades2Patricia Heyn3Gabriela Silva Santos4Karsten Motzler5Anja Zeigerer6Romina Bester7Ulrike Protzer8Florian Schelter9Mirko Wagner10Thomas Carell11Alexander Hruscha12Bettina Schmid13Oscar Yanes14Robert Schneider15Institute of Functional Epigenetics, Helmholtz Zentrum München, 85764 Neuherberg, GermanyInstitute of Functional Epigenetics, Helmholtz Zentrum München, 85764 Neuherberg, GermanyUniversitat Rovira i Virgili, Department of Electronic Engineering, IISPV, Tarragona, Spain; CIBER on Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, SpainInstitute of Functional Epigenetics, Helmholtz Zentrum München, 85764 Neuherberg, GermanyInstitute of Functional Epigenetics, Helmholtz Zentrum München, 85764 Neuherberg, GermanyInstitute for Diabetes and Cancer, Helmholtz Center Munich, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, GermanyInstitute for Diabetes and Cancer, Helmholtz Center Munich, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, GermanyInstitute of Virology, Technical University of Munich, School of Medicine/Helmholtz Munich, Trogerstr. 30, 81675 Munich, GermanyInstitute of Virology, Technical University of Munich, School of Medicine/Helmholtz Munich, Trogerstr. 30, 81675 Munich, GermanyLudwig-Maximilians-Universität München, Institute for Chemical Epigenetics Munich, Butenandtstr. 5-13, 81377 Munich, GermanyLudwig-Maximilians-Universität München, Institute for Chemical Epigenetics Munich, Butenandtstr. 5-13, 81377 Munich, GermanyLudwig-Maximilians-Universität München, Institute for Chemical Epigenetics Munich, Butenandtstr. 5-13, 81377 Munich, GermanyGerman Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, GermanyGerman Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, GermanyUniversitat Rovira i Virgili, Department of Electronic Engineering, IISPV, Tarragona, Spain; CIBER on Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, SpainInstitute of Functional Epigenetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Faculty of Biology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany; Corresponding author. Institute of Functional Epigenetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.Objective: Cancer cells convert more glucose into lactate than healthy cells, what contributes to their growth advantage. Pyruvate kinase (PK) is a key rate limiting enzyme in this process, what makes it a promising potential therapeutic target. However, currently it is still unclear what consequences the inhibition of PK has on cellular processes. Here, we systematically investigate the consequences of PK depletion for gene expression, histone modifications and metabolism. Methods: Epigenetic, transcriptional and metabolic targets were analysed in different cellular and animal models with stable knockdown or knockout of PK. Results: Depleting PK activity reduces the glycolytic flux and causes accumulation of glucose-6-phosphate (G6P). Such metabolic perturbation results in stimulation of the activity of a heterodimeric pair of transcription factors MondoA and MLX but not in a major reprogramming of the global H3K9ac and H3K4me3 histone modification landscape. The MondoA:MLX heterodimer upregulates expression of thioredoxin-interacting protein (TXNIP) – a tumour suppressor with multifaceted anticancer activity. This effect of TXNIP upregulation extends beyond immortalised cancer cell lines and is applicable to multiple cellular and animal models. Conclusions: Our work shows that actions of often pro-tumorigenic PK and anti-tumorigenic TXNIP are tightly linked via a glycolytic intermediate. We suggest that PK depletion stimulates the activity of MondoA:MLX transcription factor heterodimers and subsequently, increases cellular TXNIP levels. TXNIP-mediated inhibition of thioredoxin (TXN) can reduce the ability of cells to scavenge reactive oxygen species (ROS) leading to the oxidative damage of cellular structures including DNA. These findings highlight an important regulatory axis affecting tumour suppression mechanisms and provide an attractive opportunity for combination cancer therapies targeting glycolytic activity and ROS-generating pathways.http://www.sciencedirect.com/science/article/pii/S2212877823000820Pyruvate kinaseCancerROSGlycolysisThioredoxin-interacting proteinArrestins |
| spellingShingle | Anna Nieborak Saulius Lukauskas Jordi Capellades Patricia Heyn Gabriela Silva Santos Karsten Motzler Anja Zeigerer Romina Bester Ulrike Protzer Florian Schelter Mirko Wagner Thomas Carell Alexander Hruscha Bettina Schmid Oscar Yanes Robert Schneider Depletion of pyruvate kinase (PK) activity causes glycolytic intermediate imbalances and reveals a PK-TXNIP regulatory axis Molecular Metabolism Pyruvate kinase Cancer ROS Glycolysis Thioredoxin-interacting protein Arrestins |
| title | Depletion of pyruvate kinase (PK) activity causes glycolytic intermediate imbalances and reveals a PK-TXNIP regulatory axis |
| title_full | Depletion of pyruvate kinase (PK) activity causes glycolytic intermediate imbalances and reveals a PK-TXNIP regulatory axis |
| title_fullStr | Depletion of pyruvate kinase (PK) activity causes glycolytic intermediate imbalances and reveals a PK-TXNIP regulatory axis |
| title_full_unstemmed | Depletion of pyruvate kinase (PK) activity causes glycolytic intermediate imbalances and reveals a PK-TXNIP regulatory axis |
| title_short | Depletion of pyruvate kinase (PK) activity causes glycolytic intermediate imbalances and reveals a PK-TXNIP regulatory axis |
| title_sort | depletion of pyruvate kinase pk activity causes glycolytic intermediate imbalances and reveals a pk txnip regulatory axis |
| topic | Pyruvate kinase Cancer ROS Glycolysis Thioredoxin-interacting protein Arrestins |
| url | http://www.sciencedirect.com/science/article/pii/S2212877823000820 |
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