GBM cells can release glutamate to extra cellular through Xc system. I want to know that does this happen all time?
Glutamate is exported from the GBM cells in exchange for cystine via the amino acid transporter system Xc-, which features the xCT transporter subunit (also known as SLC7A11). Increased glutamate in the tumor microenvironment leads to brain edema, the main cause of death in GBM patients. Tumor microenvironment affected by the functional inhibition of xCT with administration of sulfasalazine (SSZ), one of the DMARDs for patients with rheumatoid arthritis or ulcerative colitis, has strongly suggested the pathological significance of GBM-induced neurotoxicity and its impact on the development of peritumoral brain swelling. Cysteine uptake contributes to the synthesis of glutathione (GSH), which significantly decreases the accumulation of intracellular ROS.
xCT transporter is stabilized at the cellular membrane by binding to CD44 variant 8-10 (CD44v8-10) in epithelial cancer stem cells (CSCs). Epithelial-mesenchymal transition (EMT) causes increased number of CSCs with the altered splicing pattern from CD44 variant to CD44 standard isoform. That is why some researchers make misunderstanding that mesenchymal tumor cells no longer depend on CD44v-xCT-GSH axis. However, I have demonstrated the experiments to investigate into the expression amount of xCT in U251 GBM cells by quantitative RT-PCR and WB analyses. Mesenchymal GBM cells tend to express much higher amount of xCT at the cellular membrane without CD44v8-10, in comparison with HCT-116 colon cancer cells, well-known as high level expression of CD44v8-10. That is why GBM cells robustly exhibit the released glutamate and cysteine uptake, thereby affecting the microenvironment and redox stress.
[Important References]
Nat Med. 2008 Jun;14(6):629-32. doi: 10.1038/nm1772. Epub 2008 May 11.
Small interfering RNA-mediated xCT silencing in gliomas inhibits neurodegeneration and alleviates brain edema.
Savaskan NE1, Heckel A, Hahnen E, Engelhorn T, Doerfler A, Ganslandt O, Nimsky C, Buchfelder M, Eyüpoglu IY.
Cancer Cell. 2011 Mar 8;19(3):387-400. doi: 10.1016/j.ccr.2011.01.038.
CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and therebypromotes tumor growth.
Take a look at these
http://www.ncbi.nlm.nih.gov/pubmed/23175182
http://www.ncbi.nlm.nih.gov/pubmed/19997873
Dear Samira,
I think that for GBM it is Harald Sontheimer (registered on RG) who performed the most interesting studies. Lokk at his publications on his RG profile.
Best regards
Robert
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