Human glucose-6-phosphate dehydrogenase (G6PD) gene transforms NIH 3T3 cells and induces tumors in nude mice

The main physiological function of glucose-6-phosphate dehydrogenase (G6PD) is to produce NADPH and ribose 5-phosphate, which are essential for reductive biosynthesis and nucleic acid synthesis. In normal cells, G6PD expression is tightly controlled; however, in many tumors, regulation of its expression is altered, resulting in a significant increase in G6PD activity. To investigate the potential role of G6PD in tumorigenesis, we transfected NIH 3T3 cells with human G6PD cDNA. Cells overexpressing G6PD showed altered cell morphology and exhibited tumorigenic properties. In contrast to the control cells or cells transfected with mutated G6PD cDNA, G6PD-overexpressing cells were not contact inhibited and exhibited anchorage-independent growth. They divided more quickly and induced rapidly growing, large fibrosarcomas in nude mice. Moreover, the induced tumorigenic properties were positively correlated with the level of G6PD activity. Interestingly, treatment with buthionine SR-sulfoximine (BSO), a glutathione depletion agent, decreased the colony-forming efficiency of G6PD-overexpressing cells in soft agar, which implicates that alteration of the redox balance may be involved in G6PD-induced tumorigenesis. A comparative analysis of the expression level of G6PD in a variety of human cancer cell lines was also performed. Northern- and Western-blot analyses revealed that G6PD was particularly overexpressed in human esophageal cancer cell lines. Our observations indicate that G6PD may act as a potential oncogene, whose overexpression plays a critical role in neoplastic transformation.