The mechanism(s) by which alpha (alpha) particles like those emitted by radon and radon progeny cause cancer are not well understood. Recent evidence suggests that one or more components of the process may involve the induction of mechanisms in cells that do not receive direct exposure to alpha particles. These so called """"""""bystander effects"""""""" can be mediated via fluid-phase, extracellular factors and, perhaps, direct cell-cell communications. As examples, low doses of alpha particles can cause excessive sister chromatid exchanges and increases in intracellular reactive oxygen species (ROS) via mechanisms that involve transmissible, extracellular factors present in alpha- irradiated culture medium and in the supernatants from alpha-irradiated cells. More recent evidence has been obtained for other low dose alpha particle-associated bystander effects that are also mediated by extracellular factors, which appear to include ROS, transforming growth factor-beta and interleukin-8. One of these effects is a decrease in basal levels of the tumor suppressor protein p53 in cells that have been pretreated with supernatants from alpha-irradiated cells. A second, potentially related bystander effect is that cells that have been treated with supernatants from alpha-irradiated cells show, relative to control cells, diminutions in p53 and p21Waf-1 protein elevations after subsequent exposure to alpha particles. New evidence also suggests that exposure of cells to low dose alpha particles or supernatants from alpha-irradiated cells can enhance cell proliferation. Based on these findings, the Specific Aims of the project are: 1) To determine the mechanistic relationship between the alpha particle-associated generation of reactive oxygen species (ROS) and the decreased p53 bystander effect, 2) To elucidate the molecular basis(es) for the decreased p53 bystander response, 3) To ascertain the role(s) the ROS and decreased p53 bystander effects play in regulating cell proliferation, and 4) To examine how the decreased p53 bystander response affects cell cycle arrests/delays following subsequent exposure to alpha particles and gamma-rays. In the proposed investigations, which involve cellular, biochemical, and molecular approaches conducted mainly with primary cultures of normal human lung fibroblasts and bronchial epithelial cells, we will test hypotheses that mechanistically link the alpha particle-associated ROS and the decreased p53 bystander effects, cell proliferation, and cell p53 and cell cycle responses to DNA damaging ionizing radiations, with the ultimate goal being to the elucidate mechanisms that are involved in vivo in airway cell hyperplasia and bronchogenic carcinoma in response to exposure to radon/radon progeny and other alpha-emitters.
| Iyer, Rashi; Lehnert, Bruce E (2002) Alpha-particle-induced increases in the radioresistance of normal human bystander cells. Radiat Res 157:3-7 |
| Deshpande, Alina; Narayanan, Padma K; Lehnert, Bruce E (2002) Silica-induced generation of extracellular factor(s) increases reactive oxygen species in human bronchial epithelial cells. Toxicol Sci 67:275-83 |
| Goldberg, Zelanna; Lehnert, Bruce E (2002) Radiation-induced effects in unirradiated cells: a review and implications in cancer. Int J Oncol 21:337-49 |
| Iyer, Rashi; Lehnert, Bruce E (2002) Low dose, low-LET ionizing radiation-induced radioadaptation and associated early responses in unirradiated cells. Mutat Res 503:1-9 |
| Iyer, R; Lehnert, B E (2000) Effects of ionizing radiation in targeted and nontargeted cells. Arch Biochem Biophys 376:14-25 |
| Iyer, R; Lehnert, B E; Svensson, R (2000) Factors underlying the cell growth-related bystander responses to alpha particles. Cancer Res 60:1290-8 |
