Abstract 5422: Human GBM-derived brain tumor stem cells resist glycolysis inhibition through Glucose 6 phosphatase: a potential clinical implication in the treatment of recurrent brain tumors.
Authors: Abbadi Sara , Guerrero-Cazares Hugo , Abutaleb Ameer , Smith Chris L. , Ruff William , Schiller Jennifer , Levchenko Andre , Quinones-Hinojosa Alfredo 
Published: August 2014

Glioblastomas (GBMs) are characterized by a very aggressive behavior and a heterogeneous presentation that includes proliferative, invasive, and necrotic areas. The rapid expansion of GBMs frequently outgrowths the blood supply, originating hypoxic and necrotic regions, which induces metabolic changes in the tumor cells. In a survival adaptation response, tumor cells adjust their glucose metabolism to an anaerobic glycolysis, even in the presence of oxygen. This is known as the Warburg effect and it is enhanced in Brain Tumor Stem Cells (BTSCs), the cellular sub-population considered to be responsible for the tumor origin and recurrence. Glycolysis inhibition can be achieved using glucose analogues like 2-deoxyglucose (2DG). We have previously demonstrated that 2DG treatment of BTSCs induces a decrease in cell proliferation and an increase in cell death and neuronal differentiation. Nevertheless, some BTSC cells are able to survive glycolysis inhibition and recover their aggressive phenotype which might be related to brain tumor recurrence. Here we studied the tumorigenic behavior of human GBM-derived primary BTSCs after recovery from glycolysis inhibition. We observed that cells which were pretreated with 2DG and subsequently allowed to recover for 72h in glucose-containing media, exhibited a more aggressive phenotype; including an increased migration, invasion, and proliferation capability; as well as MMP2 and nestin overexpression. Some of these features recapitulate what occurs in recurrent brain tumors. In studying the potential molecular mechanisms responsible for this behavior, we observed an increased expression of glucose-6-phosphatase isoform α (G6PC) in our primary GBM cells when compared to normal brain. Moreover, 2DG treatment induced an increase in the expression of this isoform. G6PC is a key glucose homeostasis enzyme not previously reported in brain tissue. In addition, when G6PC was inhibited, either pharmacologically (with chlorogenic acid) or genetically (with shRNA), we observed that the recovery capacity of GBM cells was significantly reduced. This was evident by a decrease in their proliferation, migration, and invasion ability, as well as by a decrease in HIF1α, pSTAT3 protein, MMP2 gene expression. In summary, we report for the first time the expression of G6PC in GBM cells. This specific isoform is not expressed in normal brain parenchyma, which makes it a very attractive target for anticancer therapy. Our results suggest a role of G6PC in promoting a mechanism of GBM cell recovery from glycolysis inhibition. By unraveling these mechanisms we describe an important therapeutic target that could impact the recurrence ability of brain tumors.

Citation Format: Sara Abbadi, Hugo Guerrero-Cazares, Ameer Abutaleb, Chris L. Smith, William Ruff, Jennifer Schiller, Andre Levchenko, Alfredo Quinones-Hinojosa. Human GBM-derived brain tumor stem cells resist glycolysis inhibition through Glucose 6 phosphatase: a potential clinical implication in the treatment of recurrent brain tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5422. doi:10.1158/1538-7445.AM2013-5422