Journal Article

DZNE-2023-00725

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Depletion of pyruvate kinase (PK) activity causes glycolytic intermediate imbalances and reveals a PK-TXNIP regulatory axis.

Nieborak, A. ; Lukauskas, S. ; Capellades, J. ; Heyn, P. ; Santos, G. S. ; Motzler, K. ; Zeigerer, A. ; Bester, R. ; Protzer, U. ; Schelter, F. ; Wagner, M. ; Carell, T. ; Hruscha, A.DZNE* ; Schmid, B.DZNE* ; Yanes, O. ; Schneider, R.

2023
Elsevier Oxford [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.molmet.2023.101748

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.

Keyword(s): Animals (MeSH) ; Pyruvate Kinase: genetics (MeSH) ; Reactive Oxygen Species (MeSH) ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors: metabolism (MeSH) ; Neoplasms: genetics (MeSH) ; Neoplasms: metabolism (MeSH) ; Thioredoxins: chemistry (MeSH) ; Thioredoxins: metabolism (MeSH) ; Arrestins ; Cancer ; Glycolysis ; Metabolic flux ; Pyruvate kinase ; ROS ; Thioredoxin-interacting protein ; Pyruvate Kinase ; Reactive Oxygen Species ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; Thioredoxins

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Contributing Institute(s):

1. Fish Core Unit (AG Schmid)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2023

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Database coverage:
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