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@ARTICLE{Nieborak:259129,
      author       = {Nieborak, Anna and Lukauskas, Saulius and Capellades, Jordi
                      and Heyn, Patricia and Santos, Gabriela Silva and Motzler,
                      Karsten and Zeigerer, Anja and Bester, Romina and Protzer,
                      Ulrike and Schelter, Florian and Wagner, Mirko and Carell,
                      Thomas and Hruscha, Alexander and Schmid, Bettina and Yanes,
                      Oscar and Schneider, Robert},
      title        = {{D}epletion of pyruvate kinase ({PK}) activity causes
                      glycolytic intermediate imbalances and reveals a
                      {PK}-{TXNIP} regulatory axis.},
      journal      = {Molecular metabolism},
      volume       = {74},
      issn         = {2212-8778},
      address      = {Oxford [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DZNE-2023-00725},
      pages        = {101748},
      year         = {2023},
      abstract     = {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.Epigenetic, transcriptional and metabolic targets
                      were analysed in different cellular and animal models with
                      stable knockdown or knockout of PK.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.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.},
      keywords     = {Animals / Pyruvate Kinase: genetics / Reactive Oxygen
                      Species / Basic Helix-Loop-Helix Leucine Zipper
                      Transcription Factors: metabolism / Neoplasms: genetics /
                      Neoplasms: metabolism / Thioredoxins: chemistry /
                      Thioredoxins: metabolism / Arrestins (Other) / Cancer
                      (Other) / Glycolysis (Other) / Metabolic flux (Other) /
                      Pyruvate kinase (Other) / ROS (Other) /
                      Thioredoxin-interacting protein (Other) / Pyruvate Kinase
                      (NLM Chemicals) / Reactive Oxygen Species (NLM Chemicals) /
                      Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
                      (NLM Chemicals) / Thioredoxins (NLM Chemicals)},
      cin          = {AG Schmid},
      ddc          = {610},
      cid          = {I:(DE-2719)1140002},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37290673},
      pmc          = {pmc:PMC10336528},
      doi          = {10.1016/j.molmet.2023.101748},
      url          = {https://pub.dzne.de/record/259129},
}