TY  - JOUR
AU  - Nieborak, Anna
AU  - Lukauskas, Saulius
AU  - Capellades, Jordi
AU  - Heyn, Patricia
AU  - Santos, Gabriela Silva
AU  - Motzler, Karsten
AU  - Zeigerer, Anja
AU  - Bester, Romina
AU  - Protzer, Ulrike
AU  - Schelter, Florian
AU  - Wagner, Mirko
AU  - Carell, Thomas
AU  - Hruscha, Alexander
AU  - Schmid, Bettina
AU  - Yanes, Oscar
AU  - Schneider, Robert
TI  - Depletion of pyruvate kinase (PK) activity causes glycolytic intermediate imbalances and reveals a PK-TXNIP regulatory axis.
JO  - Molecular metabolism
VL  - 74
SN  - 2212-8778
CY  - Oxford [u.a.]
PB  - Elsevier
M1  - DZNE-2023-00725
SP  - 101748
PY  - 2023
AB  - 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.
KW  - Animals
KW  - Pyruvate Kinase: genetics
KW  - Reactive Oxygen Species
KW  - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors: metabolism
KW  - Neoplasms: genetics
KW  - Neoplasms: metabolism
KW  - Thioredoxins: chemistry
KW  - Thioredoxins: metabolism
KW  - Arrestins (Other)
KW  - Cancer (Other)
KW  - Glycolysis (Other)
KW  - Metabolic flux (Other)
KW  - Pyruvate kinase (Other)
KW  - ROS (Other)
KW  - Thioredoxin-interacting protein (Other)
KW  - Pyruvate Kinase (NLM Chemicals)
KW  - Reactive Oxygen Species (NLM Chemicals)
KW  - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (NLM Chemicals)
KW  - Thioredoxins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37290673
C2  - pmc:PMC10336528
DO  - DOI:10.1016/j.molmet.2023.101748
UR  - https://pub.dzne.de/record/259129
ER  -