Priority Research Papers:
Metabolic reprogramming of glioblastoma cells by L-asparaginase sensitizes for apoptosis in vitro and in vivo
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Georg Karpel-Massler1, Doruntina Ramani1, Chang Shu1, Marc-Eric Halatsch3, Mike-Andrew Westhoff4, Jeffrey N. Bruce2, Peter Canoll1 and Markus D. Siegelin1
1 Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York, United States of America
2 Department of Neurological Surgery, Columbia University Medical Center, New York, New York, United States of America
3 Department of Neurosurgery, Ulm University Medical Center, Ulm, Germany
4 Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
Markus D. Siegelin, email:
Keywords: apoptosis, L-asparaginase, ABT263, TRAIL, glioblastoma
Received: February 29, 2016 Accepted: April 26, 2016 Published: May 09, 2016
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.
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