The Classical Apoptotic Adaptor FADD Regulates Glycolytic Capacity in Acute Lymphoblastic Leukemia

The Fas-associated death domain (FADD) has long been regarded as a crucial adaptor protein in the extrinsic apoptotic pathway. Despite the non-apoptotic function of FADD is gradually being discovered and confirmed, its corresponding physiological and pathological significance is still unclear. Based...

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Bibliographic Details
Published in:International journal of biological sciences 2022-01, Vol.18 (8), p.3137-3155
Main Authors: Zhou, Wenzhao, Lai, Yueyang, Zhu, Jianhui, Xu, Xuebo, Yu, Wenliang, Du, Zengzheng, Wu, Leyang, Zhang, Xuerui, Hua, Zichun
Format: Article
Language:English
Subjects:
Acute lymphoblastic leukemia
Adapters
Apoptosis
Apoptosis - genetics
By products
Cancer
Cell cycle
Cell proliferation
CRISPR
Cytochrome
Enzymes
Etoposide
FADD protein
Fas-Associated Death Domain Protein - genetics
Fas-Associated Death Domain Protein - metabolism
Flow cytometry
Gene expression
Glucose
Glycolysis
Glycolysis - genetics
Humans
Hypersensitivity
Jurkat Cells
Leukemia
Lymphocytes T
Membranes
Metabolic pathways
Metabolism
Mitochondria
Phosphorylation
Plasmids
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Proteins
Proteomics
Research Paper
Respiration
Single-nucleotide polymorphism
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Summary:The Fas-associated death domain (FADD) has long been regarded as a crucial adaptor protein in the extrinsic apoptotic pathway. Despite the non-apoptotic function of FADD is gradually being discovered and confirmed, its corresponding physiological and pathological significance is still unclear. Based on the database of GWAS catalog and GTEx Portal, 17 SNPs associated with leukemia susceptibility were found to be linked to FADD expression. We then investigated a regulatory role of FADD in T-acute lymphoblastic leukemia (T-ALL) using Jurkat cells as a model. Jurkat cells stably depleted of FADD (FADD Jurkat) expression exhibited dampened proliferation, hypersensitivity to Etoposide-induced intrinsic apoptosis whereas near total resistance to TRAIL-induced extrinsic apoptosis. Comparison between wild type and FADD Jurkat cells using iTRAQ-based proteomics revealed considerably altered expression spectrum of genes, and led us to focus on metabolic pathways. Investigation of glycolytic and mitochondrial pathways and relevant enzymes revealed that FADD knockout triggered a metabolic shift from glycolysis to mitochondrial respiration in Jurkat cells. Re-expression of FADD in FADD Jurkat cells partially rescued glycolytic capacity. FADD loss triggers global metabolic reprogramming in Jurkat cells and therefore remains as a potential druggable target for ALL treatment.
ISSN:1449-2288
1449-2288
DOI:10.7150/ijbs.68016