Year: 2018
Type: article
Abstract: It has long been recognized that sugar transporters are often upregulated in cancers and the upregulation of the Glut3 glucose/galactose transporter in glioma is well described. We have identified that Glut14, the testicular-specific glucose/galactose transporter is also upregulated in GBM, and that levels of Glut3/Glut14 predict patient outcome. We used a Glut3/Glut14 substrate and glucose/galactose analogue, 4-deoxy 4-fluoro Galactose (4D4FG), to inhibit glycan synthesis in glioma, in vitro and in vivo. As 4D4FG is a potent inhibitor of both UDP-glucose 4-epimerase (GALE) and UDP-glucose 6-dehydrogenase (UGDH), we were able to observe aberrant glycan synthesis in glioma exposed to 4D4FG. Perturbation of glycan synthesis correlated with gliomal cell death in vitro, and is accompanied by loss of nuclear localization of glycosylated proteins. In a flank mouse model of primary GBM we compared the effects of three cycles of i.p. 4D4FG with vehicle. We found that 4D4FG initially caused a small shrinkage of tumors, and then slowed tumor growth by 35%, with respect to the controls. Using the upregulation of gliomal sugar transporters to differentially target cancer glycan metabolism is clearly deleterious to glioma. Anti-metabolites like 4D4FG will never be first-line chemotherapeutics in cancer treatment. However, such anti-metabolites may be very usefully used to pre-stress glioma, prior to chemoradiation, to differentially sensitize the tumor to conventional treatment.
Source: Neuro-Oncology
Authors: Martyn Sharpe, David Baskin
Institution: Houston Methodist
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2900448877