THE ROLE OF GLUTAMINE AND MEVALONATE PATHWAY IN AFFECTING THE STEMNESS AND VIABILITY OF GLIOBLASTOMA STEM CELLS

Glioblastoma (GBM) remains the deadliest form of brain tumors. The poor prognosis of glioblastoma patients is associated with a high rate of relapse after therapy. It has been suggested that the presence of cancer stem cells, which are relatively resistant to radiation and chemotherapy, may play a significant role in the recurrence of brain tumor. Understanding the biological property of glioblastoma stem cells is important to develop effective therapeutic strategies for glioblastoma. In vitro, glioblastoma stem cells cultured in serum-free medium form self-renewing neurospheres, express the neural stem marker CD133, and are highly tumorigenic. On the other hand, in the presence of fetal bovine serum (FBS), the glioblastoma stem cells undergo differentiation. In this study we used glioblastoma stem cells, GSC11 and GSC23, previously isolated from glioblastoma patients and expressed stem cell markers CD133, Olig2 and SOX2, to explore their bioenergetics by monitoring the oxygen consumption as an indication of mitochondrial respiration cultured in serum-free medium in comparison with that incubated in medium containing FBS. We found that GSC11 and GSC23 stem cells exhibited low mitochondrial respiration when cultured in stem cell medium. Upon exposure to FBS mitochondrial respiration increased significantly. Metabolic changes were also observed. Furthermore, we found that glutamine uptake was higher in GBM stem cells compared with FBS induced cells. Additionally, treatment of the cells with Compound 968, a glutaminase inhibitor, depleted the cells from the CD133 marker, slowed proliferation and limited growth on soft agar. Moreover, GBM stem cells showed an increase in the expression of genes related to the mevalonate pathway. We also found that simvastatin, an inhibitor of the mevalonate pathway, induced GBM stem cells death. This study showed mitochondria metabolic reprograming of GBM stem cells during differentiation. It also showed the importance of glutamine in maintaining CD133 expression and GBM stem cells growth. Lastly, the study showed that mevalonate pathway is a target to eliminate GBM stem cells