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* This work was supported in part by American Cancer Society Grant BE-131A (to R. C. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ‡ Recipient of National Service Research Award DK09265-02.
The intracellular redox potential, which is determined by the level of oxidants and reductants, has been shown to play an important role in the regulation of cell growth. The principal intracellular reductant is NADPH, which is mainly produced by the pentose phosphate pathway through the actions of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, and by 6-phosphogluconate dehydrogenase. Previous research has suggested that an increase in G6PD activity is important for cell growth. In this article, we suggest that G6PD activity plays a critical role in cell growth by providing NADPH for redox regulation. The results show the following: 1) inhibition of G6PD activity abrogated growth factor stimulation of [3H]thymidine incorporation in all cell lines tested; 2) overexpression of G6PD stimulated cell growth, as measured by an increase in [3H]thymidine incorporations as compared with cells transfected with vector alone; 3) inhibition of G6PD caused cells to be more susceptible to the growth inhibitory effects of H2O2; 4) inhibition of G6PD led to a 30–40% decrease in the NADPH/NADP ratio; and 5) inhibition of G6PD inhibited cell anchorage and significantly decreased the growth-related stimulation of tyrosine phosphorylation.
Intracellular redox regulation is important for the regulation of cell growth (
Previous research has shown an association between the stimulation of cell growth and increased activity of the PPP that occurs over hours to days. For example, 1) kidney hypertrophy due to a variety of growth stimuli (e.g. unilateral nephrectomy or diabetes mellitus) is associated with an increased activity of the PPP due to increased G6PD activity (
). These findings suggest that G6PD activity is important for cell growth.
Research from our laboratory and others have shown that, in addition to the long term stimulation of G6PD by growth factors, there is a stimulation of G6PD activity that occurs within seconds to minutes following exposure to growth factors (
). Specifically, our laboratory has shown that following stimulation of rat renal cells to grow using epidermal growth factor (EGF), an increase in the activity of G6PD was observed within seconds, maximal at 1 min, and back to base-line level in 60 min (
). In a search for the mechanism of this rapid activation of G6PD, we discovered that G6PD, an enzyme thought to exist unbound in the cytoplasm, is probably bound to an intracellular structure and translocates following growth factor stimulation (
The previous work implies that there may be a mechanistic relationship between cell growth and G6PD activity. This report is designed to more directly assess the importance of G6PD activity on cell growth. The effects of both increases in G6PD activity via overexpression of G6PD and decreases in G6PD activity via the use of a G6PD inhibitor were used to address the importance and possible roles that G6PD may play in cell growth. The data suggest that proper G6PD activity is important for regulation of intracellular redox level during cell growth. The data further suggest that G6PD activity is important for proper cell anchorage and growth factor-stimulated tyrosine phosphorylation.