Low dose of 2-deoxy-D-glucose kills acute lymphoblastic leukemia cells and reverses glucocorticoid resistance via N-linked glycosylation inhibition under normoxia

Gu, Ling; Yi, Zhihui; Zhang, Yanle; Ma, Zhigui; Zhu, Yiping; Gao, Ju

doi:10.18632/oncotarget.16046

Cited by 22 publications

(24 citation statements)

References 47 publications

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“…(2DG), a competitive inhibitor of glucose metabolism, on Crk/Crkl deficient or control MEFs (Gu et al, 2017). We noted that when cultured in a glucose-controlled condition (5 mM glucose with 10% dialyzed FBS), a range of 2DG concentrations induced blebbing cell morphology identified by cell staining with CellMask, DAPI, and antivinculin ( Fig S9).…”

Section: Crk/crkl Deficiency and Glucose Restriction Lead To Cell Memmentioning

confidence: 98%

Essential role of theCrkfamily-dosage in DiGeorge-like anomaly and metabolic homeostasis

Imamoto

et al. 2020

Life Sci. Alliance

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CRK and CRKL (CRK-like) encode adapter proteins with similar biochemical properties. Here, we show that a 50% reduction of the family-combined dosage generates developmental defects, including aspects of DiGeorge/del22q11 syndrome in mice. Like the mouse homologs of two 22q11.21 genes CRKL and TBX1, Crk and Tbx1 also genetically interact, thus suggesting that pathways shared by the three genes participate in organogenesis affected in the syndrome. We also show that Crk and Crkl are required during mesoderm development, and Crk/Crkl deficiency results in small cell size and abnormal mesenchyme behavior in primary embryonic fibroblasts. Our systems-wide analyses reveal impaired glycolysis, associated with low Hif1a protein levels as well as reduced histone H3K27 acetylation in several key glycolysis genes. Furthermore, Crk/Crkl deficiency sensitizes MEFs to 2-deoxy-D-glucose, a competitive inhibitor of glycolysis, to induce cell blebbing. Activated Rapgef1, a Crk/Crkl-downstream effector, rescues several aspects of the cell phenotype, including proliferation, cell size, focal adhesions, and phosphorylation of p70 S6k1 and ribosomal protein S6. Our investigations demonstrate that Crk/Crkl-shared pathways orchestrate metabolic homeostasis and cell behavior through widespread epigenetic controls.

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Section: Crk/crkl Deficiency and Glucose Restriction Lead To Cell Memmentioning

confidence: 98%

Essential role of theCrkfamily-dosage in DiGeorge-like anomaly and metabolic homeostasis

Imamoto

et al. 2020

Life Sci. Alliance

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“…2-Deoxyglucose (2DG) is a non-metabolizable glucose analog and inhibitor of HK used to shut down glycolysis since the first steps. Despite the safety of this drug in cancer patients and its efficiency beyond glycolysis inhibition in cancer cells ( 102 – 104 ), 2DG has also been shown to impair the metabolism of T cells, which results in decreased secretion of cytokines and reduced T cell antitumor function that may be critical for therapeutic success ( 105 ). Dichloroacetate (DCA) is another drug targeting cancer cell metabolism which showed conflicting results.…”

Section: Targeting Metabolism For Efficient Immunotherapymentioning

confidence: 99%

Targeting Tumor Metabolism: A New Challenge to Improve Immunotherapy

2018

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Currently, a marked number of clinical trials on cancer treatment have revealed the success of immunomodulatory therapies based on immune checkpoint inhibitors that activate tumor-specific T cells. However, the therapeutic efficacy of cancer immunotherapies is only restricted to a small fraction of patients. A deeper understanding of key mechanisms generating an immunosuppressive tumor microenvironment (TME) remains a major challenge for more effective antitumor immunity. There is a growing evidence that the TME supports inappropriate metabolic reprogramming that dampens T cell function, and therefore impacts the antitumor immune response and tumor progression. Notably, the immunosuppressive TME is characterized by a lack of crucial carbon sources critical for T cell function and increased inhibitory signals. Here, we summarize the basics of intrinsic and extrinsic metabolic remodeling and metabolic checkpoints underlying the competition between cancer and infiltrating immune cells for nutrients and metabolites. Intriguingly, the upregulation of tumor programmed death-L1 and cytotoxic T lymphocyte-associated antigen 4 alters the metabolic programme of T cells and drives their exhaustion. In this context, targeting both tumor and T cell metabolism can beneficially enhance or temper immunity in an inhospitable microenvironment and markedly improve the success of immunotherapies.

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“…Since prednisolone‐resistant cells have higher consumption of glucose, targeting glycolysis with 2‐DG is a rationale therapeutic approach in cALL. Thus, low‐dose 2‐DG leads to apoptosis and reverses GC resistance through inhibition of N‐linked glycosylation primarily in childhood T‐ALL cell lines 91 . 2‐DG in combination with inhibition of the anti‐apoptotic protein MCL1 can reduce leukemia cell survival and resensitize cALL cells to prednisolone in vitro 92 .…”

Section: Cell Metabolism In Callmentioning

confidence: 99%

Metabolic reprogramming in childhood acute lymphoblastic leukemia

Sbirkov

Burnusuzov

Sarafian

2020

Pediatric Blood & Cancer

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The first observations of altered metabolism in malignant cells were made nearly 100 years ago and therapeutic strategies targeting cell metabolism have been in clinical use for several decades. In this review, we summarize our current understanding of cell metabolism dysregulation in childhood acute lymphoblastic leukemia (cALL). Reprogramming of cellular bioenergetic processes can be expected in the three distinct stages of cALL: at diagnosis, during standard chemotherapy, and in cases of relapse. Upregulation of glycolysis, dependency on anaplerotic energy sources, and activation of the electron transport chain have all been observed in cALL.While the current treatment strategies are tackling some of these aberrations, cALL cells are likely to be able to rewire their metabolism in order to escape therapy, which may contribute to a refractory disease and relapse. Finally, here we focus on novel therapeutic approaches emerging from our evolving understanding of the alterations of different metabolic networks in lymphoblasts. K E Y W O R D SBioenergetics, cALL, cell metabolism, therapy

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Low dose of 2-deoxy-D-glucose kills acute lymphoblastic leukemia cells and reverses glucocorticoid resistance via N-linked glycosylation inhibition under normoxia

Cited by 22 publications

References 47 publications

Essential role of theCrkfamily-dosage in DiGeorge-like anomaly and metabolic homeostasis

Essential role of theCrkfamily-dosage in DiGeorge-like anomaly and metabolic homeostasis

Targeting Tumor Metabolism: A New Challenge to Improve Immunotherapy

Metabolic reprogramming in childhood acute lymphoblastic leukemia

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