TKTL1 Knockdown Impairs Hypoxia-Induced Glucose-6-phosphate Dehydrogenase and Glyceraldehyde-3-phosphate Dehydrogenase Overexpression

Increased expression of transketolase (TKT) and its isoform transketolase-like-1 (TKTL1) has been related to the malignant leukemia phenotype through promoting an increase in the non-oxidative branch of the pentose phosphate pathway (PPP). Recently, it has also been described that TKTL1 can have a r...

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Published in:International journal of molecular sciences Vol. 23; no. 7; p. 3574
Main Authors: Baptista, Inês, Karakitsou, Effrosyni, Cazier, Jean-Baptiste, Günther, Ulrich L., Marin, Silvia, Cascante, Marta
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 25.03.2022
MDPI
Subjects:
Adaptation
Cancer therapies
Cell culture
Cell growth
Dehydrogenases
Enzymes
Gene expression
Glucose
Glucose - metabolism
Glucosephosphate Dehydrogenase - genetics
Glucosephosphate Dehydrogenase - metabolism
Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
Glyceraldehyde-3-Phosphate Dehydrogenases - metabolism
Humans
Hypoxia
Kinases
Leukemia
Leukemia, Myeloid, Acute
Metabolism
Metabolites
Pentose Phosphate Pathway - genetics
Transketolase - genetics
Transketolase - metabolism
AML
glucose-6-phosphate dehydrogenase
hypoxia
leukemia
transcriptomics
metabolism
glyceraldehyde-3-phosphate dehydrogenase
transketolase-like 1
pentose phosphate pathway
ISSN:1422-0067, 1661-6596, 1422-0067
Online Access:Get full text
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Summary:Increased expression of transketolase (TKT) and its isoform transketolase-like-1 (TKTL1) has been related to the malignant leukemia phenotype through promoting an increase in the non-oxidative branch of the pentose phosphate pathway (PPP). Recently, it has also been described that TKTL1 can have a role in survival under hypoxic conditions and in the acquisition of radio resistance. However, TKTL1’s role in triggering metabolic reprogramming under hypoxia in leukemia cells has never been characterized. Using THP-1 AML cells, and by combining metabolomics and transcriptomics techniques, we characterized the impact of TKTL1 knockdown on the metabolic reprogramming triggered by hypoxia. Results demonstrated that TKTL1 knockdown results in a decrease in TKT, glucose-6-phosphate dehydrogenase (G6PD) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activities and impairs the hypoxia-induced overexpression of G6PD and GAPDH, all having significant impacts on the redox capacity of NADPH- and NADH-related cells. Moreover, TKTL1 knockdown impedes hypoxia-induced transcription of genes encoding key enzymes and transporters involved in glucose, PPP and amino acid metabolism, rendering cells unable to switch to enhanced glycolysis under hypoxia. Altogether, our results show that TKTL1 plays a key role in the metabolic adaptation to hypoxia in THP-1 AML cells through modulation of G6PD and GAPDH activities, both regulating glucose/glutamine consumption and the transcriptomic overexpression of key players of PPP, glucose and amino acids metabolism.
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These authors contributed equally to this work.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms23073574