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

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 synthesis reduced autophagosome content of ALL cells, and dm-αkg also rescued cell viability. These data suggest that glutamine synthesis affects autophagy and possibly onset of cell death in response to GCs, which should be further explored to understand mechanism of action and possible sources of resistance.

Current Outlook on Autophagy in Human Leukemia: Foe in Cancer Stem Cells and Drug Resistance, Friend in New Therapeutic Interventions

“…Standard treatment of B-ALL is the administration of synthetic glucocorticoids (GC) to slow down cellular glucose intake and induce cell death [127]. Following GC treatment in B-ALL, there is a reduction in glucose and glutamine cellular intake but unexpectedly an increase of glutamine synthesis [128]. Dyczynski et al showed that in the absence of normal nutrient intake, there is increased autophagic flux to catabolically make up for the lost nutrients; a byproduct of this catabolism, ammonia, is then utilized by glutamate–ammonia ligase to synthesize glutamine intracellularly, allowing the cells to provide their own glucose supply [128].…”

Transcriptome Profiling and Cytological Assessments for Identifying Regulatory Pathways Associated With Diorcinol N-Induced Autophagy in A3 Cells

“…While tremendous progress has been made in the treatment of pediatric ALL, the success rate of current treatments is much more modest in adults ( Aldoss and Stein, 2018 ). Hence, new therapeutic agents are urgently needed for ALL therapy ( Thu Huynh and Bergeron, 2017 ; Dyczynski et al., 2018a ). The antifungal, anticancer, and antinociceptive effects of diorcinol have been investigated in previous studies ( Gao et al., 2013 ; Li et al., 2015 ; Zhuravleva et al., 2016 ; Li et al., 2018 ; Zhang et al., 2018 ).…”

Metabolic reprogramming in childhood acute lymphoblastic leukemia

“…The functional impact of GCs on cALL cell metabolism in vitro is demonstrated by proving that GCs reduce nucleotide, polyamine, and fatty acid synthesis. Concomitantly, GCs induce glutamine and phosphatidylcholine synthesis as well as FAO shifting the entire mitochondrial fuel programme 57 . Furthermore, dexamethasone can decrease glycolysis and enhance OxPhos and mitochondrial turnover through autophagy in pediatric T‐ALL cell lines 58 …”