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.