"GO OR GROW" - LINKS BETWEEN CELLULAR FUNCTION, GLUCOSE METABOLISM AND GLIOMA MICROENVIRONMENT

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Abstract

BACKGROUND: The "go or grow" hypothesis states that glioma cells either favor proliferation at the expense of migration or migration at the expense of proliferation. This dichotomy is regulated by multiple factors, including ECM components, microRNAs and transcription factors. We recently found that glucose metabolism also contributes to this dichotomy and discovered an oxygen-dependent metabolic switch between the pentose phosphate pathway (PPP) and the preparatory phase of glycolysis in glioma stem-like cells and tissues, which is associated with distinct phenotypes. Expression of glycolysis enzymes and glycolytic flux are increased by hypoxia and associated with cell migration, whereas the PPP is favored by oxygenation and associated with proliferation (Kathagen et al., Acta Neuropathol 2013). Building on these findings, we now studied the causal regulatory involvement of glycolysis versus the PPP in migration versus proliferation. METHODS: Enzyme inhibitors and lentiviral shRNA transduction were used to modulate the expression and activity of enzymes of glycolysis and the PPP. Proliferation, migration and clonogenicity were analyzed in vitro. Tumor initiation and growth were studied in an orthotopic nude mouse model. RESULTS: We identified G6PD and ALDOC as the most strongly inversely regulated enzymes of the PPP and glycolysis, respectively. Stable knockdown of G6PD, the first and key regulatory PPP enzyme, resulted in strikingly reduced proliferation but increased migration of GS cells. Conversely, knockdown of ALDOC inhibited migration while favoring proliferation. Similar results were obtained using enzyme inhibitors. The G6PD inhibitor 6-aminonicotinamide inhibited proliferation while stimulating migration, whereas erythrose-4-phosphate, an inhibitor of the glycolysis enzyme glucose-6-phosphate-isomerase (GPI) decreased migration. 2-deoxyglucose, a hexokinase inhibitor inhibited both proliferation and migration. Knockdown of G6PD in a highly proliferative but non-invasive conventional serum-grown glioblastoma cell line resulted in prolonged survival in vivo, whereas knockdown of ALDOC shortened survival. Interestingly, GPI is also known as a secreted factor termed autocrine motility factor (AMF), which binds to the surface receptor AMFR. Hypoxia strongly increased the secretion of GPI/AMF from GS cells as well as the expression of AMFR. Recombinant human GPI/AMF stimulated the migration of GS cells even more strongly than hepatocyte growth factor, a known potent glioma cell motogen. CONCLUSIONS: By interference with key enzymes of glycolysis and the PPP we demonstrated a direct causal relevance of the two pathways for the "go or grow" behaviour of GS cells, respectively. The identification of GPI/AMF as an extraordinarily potent motogen for GS cells, explains in part the pro-migratory effect of glycolysis. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.

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