The effect of zinc status on DNA damage response in prostate epithelial cells

Abstract

Zinc is an essential mineral that has known antioxidant, anti-inflammatory and anti-proliferative properties. The prostate also contains the highest level of zinc compared to other tissues in the body. However, as the prostate becomes cancerous it loses its ability to accumulate zinc. The goal of our studies was to investigate the effect of zinc deficiency on DNA damage/stress response mechanisms and susceptibility to external DNA damaging agents (gamma irradiation) in prostate epithelial cells. Previous studies have shown zinc deficiency increases DNA strand breaks. In these studies, zinc deficiency resulted in decreased expression of Nrf2, by transcription factor array analysis, and decreased tumor suppressor p53, and mismatch repair proteins, PSM2 and MLH1, by Western blot analysis. This suggests that zinc deficiency may impair DNA damage and stress responses, and impair cell cycle regulation. When zinc deficient, zinc adequate and zinc supplemented cells were subjected to various levels of gamma irradiation (0–15Gy), zinc deficiency appeared to increase the effect of gamma irradiation as observed by cell cycle arrest and decreased cell viability. We also examined whether zinc supplementation (0–100 uM) would have a protective effect against gamma irradiation. Zinc supplementation offered slight protection against effects of gamma irradiation. In summary, zinc status may significantly modulate the cell’s ability to respond to DNA damage induced by deficiency alone or in the presence of an external DNA damaging agent. This work supported by USDA-CREES 2005-35200-15439 and Oregon Agricultural Experiment Station.