A New Pathway Promotes Adaptation of Human Glioblastoma Cells to Glucose Starvation

• Main Authors: Alberto Azzalin, Francesca Brambilla, Eloisa Arbustini, Katia Basello, Attilio Speciani, Pierluigi Mauri, Paola Bezzi, Lorenzo Magrassi
• Format: Article
• Language: English
• Published: MDPI AG 2020-05-01
• Series: Cells
• Subjects: glioblastoma cells; aerobic glycolysis; GLUT/SLC2A; SHC3; PARP1
• Online Access: https://www.mdpi.com/2073-4409/9/5/1249

Adaptation of glioblastoma to caloric restriction induces compensatory changes in tumor metabolism that are incompletely known. Here we show that in human glioblastoma cells maintained in exhausted medium, SHC adaptor protein 3 (SHC3) increases due to down-regulation of SHC3 protein degradation. This effect is reversed by glucose addition and is not present in normal astrocytes. Increased SHC3 levels are associated to increased glucose uptake mediated by changes in membrane trafficking of glucose transporters of the solute carrier 2A superfamily (GLUT/SLC2A). We found that the effects on vesicle trafficking are mediated by SHC3 interactions with adaptor protein complex 1 and 2 (AP), BMP-2-inducible protein kinase and a fraction of poly ADP-ribose polymerase 1 (PARP1) associated to vesicles containing GLUT/SLC2As. In glioblastoma cells, PARP1 inhibitor veliparib mimics glucose starvation in enhancing glucose uptake. Furthermore, cytosol extracted from glioblastoma cells inhibits PARP1 enzymatic activity in vitro while immunodepletion of SHC3 from the cytosol significantly relieves this inhibition. The identification of a new pathway controlling glucose uptake in high grade gliomas represents an opportunity for repositioning existing drugs and designing new ones.