Int J Biol Sci 2022; 18(8):3137-3155. doi:10.7150/ijbs.68016 This issue Cite

Research Paper

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

Wenzhao Zhou1*, Yueyang Lai1*, Jianhui Zhu1, Xuebo Xu1, Wenliang Yu2,3, Zengzheng Du1, Leyang Wu1, Xuerui Zhang1,3, Zichun Hua1,2,3,4✉

1. The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
2. School of Biopharmacy, China Pharmaceutical University, Nanjing, China.
3. Changzhou High-Tech Research Institute of Nanjing University and Jiangsu Target Pharma Laboratories Inc., Changzhou, China.
4. Shenzhen Research Institute of Nanjing University, Shenzhen, China.
*These two authors contributed equally.

Citation:
Zhou W, Lai Y, Zhu J, Xu X, Yu W, Du Z, Wu L, Zhang X, Hua Z. The Classical Apoptotic Adaptor FADD Regulates Glycolytic Capacity in Acute Lymphoblastic Leukemia. Int J Biol Sci 2022; 18(8):3137-3155. doi:10.7150/ijbs.68016. https://www.ijbs.com/v18p3137.htm
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Abstract

Graphic abstract

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.

Keywords: FADD, ALL, glycolysis, aerobic respiration, single nucleotide polymorphism, apoptosis


Citation styles

APA
Zhou, W., Lai, Y., Zhu, J., Xu, X., Yu, W., Du, Z., Wu, L., Zhang, X., Hua, Z. (2022). The Classical Apoptotic Adaptor FADD Regulates Glycolytic Capacity in Acute Lymphoblastic Leukemia. International Journal of Biological Sciences, 18(8), 3137-3155. https://doi.org/10.7150/ijbs.68016.

ACS
Zhou, W.; Lai, Y.; Zhu, J.; Xu, X.; Yu, W.; Du, Z.; Wu, L.; Zhang, X.; Hua, Z. The Classical Apoptotic Adaptor FADD Regulates Glycolytic Capacity in Acute Lymphoblastic Leukemia. Int. J. Biol. Sci. 2022, 18 (8), 3137-3155. DOI: 10.7150/ijbs.68016.

NLM
Zhou W, Lai Y, Zhu J, Xu X, Yu W, Du Z, Wu L, Zhang X, Hua Z. The Classical Apoptotic Adaptor FADD Regulates Glycolytic Capacity in Acute Lymphoblastic Leukemia. Int J Biol Sci 2022; 18(8):3137-3155. doi:10.7150/ijbs.68016. https://www.ijbs.com/v18p3137.htm

CSE
Zhou W, Lai Y, Zhu J, Xu X, Yu W, Du Z, Wu L, Zhang X, Hua Z. 2022. The Classical Apoptotic Adaptor FADD Regulates Glycolytic Capacity in Acute Lymphoblastic Leukemia. Int J Biol Sci. 18(8):3137-3155.

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