DHEA inhibits cell growth and induces apoptosis in BV-2 cells and the effects are inversely associated with glucose concentration in the medium

Dehydroepiandrosterone (DHEA), a major steroid secreted by the adrenal gland which decreases with age after adolescence, is available as a nutritional supplement. DHEA is known to have antiproliferative effects but the mechanism is unclear. In this study using BV-2 cells, a murine microglial cell line, we investigated the effect of DHEA on cell viability and the interaction between DHEA and glucose concentrations in the medium. We showed that DHEA inhibited cell viability and G6PD activity in a dose-dependent manner and that the effect of DHEA on cell viability was inversely associated with glucose concentrations in the medium, i.e. lowered glucose strongly enhanced the inhibition of cell viability by DHEA. DHEA inhibited cell growth by causing cell cycle arrest primarily in the G0-G1 phase, and the effect was more pronounced at zero glucose (no glucose added, G0) than high glucose (4.5 mg/ml of the medium, G4.5). Glucose deprivation also enhanced apoptosis induced by DHEA. At G4.5, DHEA did not induce formation of DNA ladder until it reached 200 μM. However, at G0, 100 μM DHEA was able to induce apoptosis, as evidenced by the formation of DNA ladder, elevation of histone-associated DNA fragmentation and increase in cells positively stained with annexin V-FITC and annexin V-FITC/propidium iodide. The interactions between DHEA and glucose support the contention that DHEA exerts its antiproliferative effects through alteration of glucose metabolism, possibly by inhibition of G6PD activity leading to decreased supply of ribose-5-phosphate for synthesis of DNA and RNA. Although DHEA is only antiproliferative at pharmacological levels, our results indicate that its antiproliferative effect can be enhanced by limiting the supply of glucose such as by energy restriction. In addition, the present study shows that glucose concentration is an important factor to consider when studying the antiproliferative and toxicological effects of DHEA.