A decrease in glucose 6-phosphate dehydrogenase activity and mRNA is an early event in phorbol ester-induced...

Redox modification of regulatory proteins implicates the glutathione redox system (GRS) in the control of gene expression. Glucose-6-phosphate dehydrogenase (G6PD) provides reducing equivalents for the GRS, and it has been suggested that high levels of G6PD in preneoplastic lesions are directly related to neoplastic transformation. We have used THP-1 human promonocytic leukemia cells, an established model of induced macrophage differentiation, to test an important corollary of this hypothesis, viz., that a decrease in G6PD activity should accompany the loss of the transformed phenotype. Phorbol 12-myristate 13-acetate (PMA) arrests the constitutive cycling of THP-1 and induces a phenotype that approaches normalcy. We measured the specific activities of the GRS enzymes, G6PD, glutathione peroxidase, and glutathione reductase during the early stages of phorbol ester-induced differentiation of THP-1 cells. We observed an 80% decrease in G6PD activity and an increase in the apparent KM for glucose 6-phosphate. In contrast, glutathione peroxidase (GPX) activity increased, while glutathione reductase (GR) activity remained essentially constant. The reduction in G6PD activity, preceding the loss of the transformed phenotype, is accompanied by a fourfold decrease in steady-state levels of G6PD mRNA. These findings are consistent with the hypothesis that high levels of G6PD are causally related to neoplastic transformations.