title: Metabolic reprogramming of glioblastoma cells by L-asparaginase sensitizes for apoptosis in vitro and in vivo.
abstract: Cancer cells display a variety of global metabolic changes, which aside from the glycolytic pathway largely involve amino acid metabolism. To ensure aggressive growth, tumor cells highly depend on amino acids, most notably due to their pivotal need of protein synthesis. In this study, we assessed the overall hypothesis that depletion of asparagine by E. coli-derived L-asparaginase might be a novel means for the therapy of one of the most recalcitrant neoplasms and for which no efficient treatment currently exists - glioblastoma (WHO grade IV). Our results suggest that certain glioma cell cultures are particularly susceptible to inhibition of proliferation by L-asparaginase, while others display a more resistant phenotype. In sensitive cells, L-asparaginase induces apoptosis with dissipation of mitochondrial membrane potential and activation of effector caspases. L-asparaginase-mediated apoptosis was accompanied by modulation of pro- and anti-apoptotic Bcl-2 family members, including Noxa, Mcl-1 and the deubiquitinase Usp9X. Given the impact of L-asparaginase on these molecules, we found that L-asparaginase potently overcomes resistance to both intrinsic apoptosis induced by the Bcl-2/Bcl-xL inhibitor, ABT263, and extrinsic apoptosis mediated by TRAIL even in glioma cells that are resistant towards L-asparaginase single treatment. RNA interference studies showed that Usp9X, Mcl-1, Noxa and Bax/Bak are involved in ABT263/L-asparaginase-mediated cell death. In vivo, combined treatment with ABT263 and L-asparaginase led to an enhanced reduction of tumor growth when compared to each reagent alone without induction of toxicity. These observations suggest that L-asparaginase might be useful for the treatment of malignant glial neoplasms.
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Georg
authors.initials: G
authors.lastname: Karpel-Massler
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Doruntina
authors.initials: D
authors.lastname: Ramani
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Chang
authors.initials: C
authors.lastname: Shu
authors.affiliation: Department of Neurosurgery, Ulm University Medical Center, Ulm, Germany.
authors.forename: Marc-Eric
authors.initials: ME
authors.lastname: Halatsch
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
authors.forename: Mike-Andrew
authors.initials: MA
authors.lastname: Westhoff
authors.affiliation: Department of Neurological Surgery, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Canoll
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Markus D
authors.initials: MD
authors.lastname: Siegelin
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001215:Asparaginase / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D013449:Sulfonamides; D001215:Asparaginase; C528561:navitoclax
keywords: ABT263; L-asparaginase; TRAIL; apoptosis; glioblastoma