Metabolic reprogramming of acute lymphoblastic leukemia cells in response to glucocorticoid treatment

Cell Death & Disease
Matheus DyczynskiRoland Nilsson

Abstract

Glucocorticoids (GCs) are metabolic hormones with immunosuppressive effects that have proven effective drugs against childhood acute lymphoblastic leukemia (ALL). Yet, the role of metabolic reprogramming in GC-induced ALL cell death is poorly understood. GCs efficiently block glucose uptake and metabolism in ALL cells, but this does not fully explain the observed induction of autophagy and cell death. Here, we have performed parallel time-course proteomics, metabolomics, and isotope-tracing studies to examine in detail the metabolic effects of GCs on ALL cells. We observed metabolic events associated with growth arrest, autophagy, and catabolism prior to onset of apoptosis: nucleotide de novo synthesis was reduced, while certain nucleobases accumulated; polyamine synthesis was inhibited; and phosphatidylcholine synthesis was induced. GCs suppressed not only glycolysis but also entry of both glucose and glutamine into the TCA cycle. In contrast, expression of glutamine-ammonia ligase (GLUL) and cellular glutamine content was robustly increased by GC treatment, suggesting induction of glutamine synthesis, similar to nutrient-starved muscle. Modulating medium glutamine and dimethyl-α-ketoglutarate (dm-αkg) to favor glutamine synth...Continue Reading

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Citations

Apr 16, 2020·Pediatric Blood & Cancer·Yordan SbirkovVictoria Sarafian
Sep 3, 2020·International Journal of Molecular Sciences·Laura AnselmiAndrea Pession
Aug 28, 2020·BMC Complementary Medicine and Therapies·Shuangshuang MaZhiyong Yu
Sep 11, 2020·Pharmacology & Therapeutics·Mengyuan Kan, Blanca E Himes
Sep 21, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Dorien ClarisseKarolien De Bosscher
Mar 30, 2021·Frontiers in Oncology·Miguel Olivas-AguirreOxana Dobrovinskaya
May 25, 2021·Metabolomics : Official Journal of the Metabolomic Society·Michel KatherArne Liebau
Dec 24, 2020·Blood Reviews·Binyan XuYuhua Li
Aug 28, 2021·International Journal of Molecular Sciences·Ioanna E Stergiou, Efstathia K Kapsogeorgou

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Methods Mentioned

BETA
FACS
fluorescence-activated cell sorting
protein assay

Software Mentioned

Cell Quest
MSGF
ProteoWizard
msConvert
Ensembl
IsobaricAnalyzer
Galaxy
Q Exactive
Percolator
OpenMS

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