title: Autophagy is required for cell survival under L-asparaginase-induced metabolic stress in acute lymphoblastic leukemia cells.
abstract: L-asparaginase has been used for more than three decades in acute lymphoblastic leukemia (ALL) patients and remains an essential drug in the treatment of ALL. Poor response to L-asparaginase is associated with increased risk of therapeutic failure in ALL. However, both the metabolic perturbation and molecular context of L-asparaginase-treated ALL cells has not been fully elucidated. Here we identify that treatment with L-asparaginase results in metabolic shutdown via the reduction of both glycolysis and oxidative phosphorylation, accompanied by mitochondrial damage and activation of autophagy. The autophagy is involved in reducing reactive oxygen species (ROS) level by eliminating injured mitochondria. Inhibition of autophagy enhances L-asparaginase-induced cytotoxicity and overcomes the acquired resistance to L-asparaginase in ALL cells. The ROS-p53-positive feedback loop is an essential mechanism of this synergistic cytotoxicity. Thus, our findings provide the rationale for the future development of combined treatment of L-asparaginase and anti-autophagy drug in ALL patients.
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.|Department of Pediatrics, Hamamatsu University School of Medicine, Shizuoka, Japan.|Bioresource Research Center, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.|Bioresource Research Center, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Inoue
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sakaguchi
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Takagi
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Mizutani
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.|Bioresource Research Center, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Inazawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001215:Asparaginase / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D013312:Stress, Physiological / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D001215:Asparaginase