Reegulation Of Glucose Metabolismby Tetrahydrobiopterin In Murine Fibroblasts

In contrast to normal differentiated cells, most proliferative cells and cancer cellsrely on aerobic glycolysis to generate the energy needed for cellular processes, aphenomenon termed the “Warburg effect”.This rapid and effective metabolicreprogramming is understoodto meet the requirement for macromolecularsynthesisaswell as producing ATP. Additionally, excreting high levels of lactate maysupport cancer cells survival, growth, and invasion by conditioning the tumormicroenvironment.Tetrahydrobiopterin (BH4) is an essential cofactor for aromatic amino acidhydroxylases and nitricoxide synthase. BH4is synthesized viaeither the de novopathway—GTP cyclohydrolase I is the rate-limiting enzymeor the pterinsalvagepathway—sepiapterin is a substrate. Oligochip arrays show that GCH has significanthigh expression in metastatic colon cancer-associated stromal fibroblasts. Recentevidence suggests that BH4plays a role in promote angiogenesis andtumor cellproliferation.We used two constructed NIH3T3-derived cell lines with expression of eitherHA-tagged human GTPCH termed “GCH-tet-off”or empty vector transfection alonetermed“Tet-off-EV”to identify the role of BH4in glucose metabolism andtumorigenicity.Results show that BH4enhanced glucose utilization and lactate production,up-regulated expression of LDHA, PDK1, MCT4, CAⅨ. Additionally,BH4synthesisleaded to the activation of PI3K/Akt/GSK3βsignaling pathway. Furthermore, BH4induced transformation of murine fibroblasts in mouse xenografts.Collectively, this study suggested the role of BH4in regulating glucosemetabolism inmurine fibroblasts, which exhibited an aerobic glycolysis metabolicphenotype.