BIOL 165 |
| Molecular mechanisms for the gamma-ionizing radiation (IR) resistance of human prostate cancer cells, PC-3, are not quite clear. The low-IR effects are primarily manifested by the generation of reactive oxygen species (ROS) and the expressions both of ROS-metabolizing antioxidant enzymes, such as Mn and CuZn superoxide dismutases (SODs) and catalase (Cat), and of the NF-kappaB transcription factor. A substantial increase in the concentrations of SODs was observed in the cells irradiated by 10 and 20 Gy relative to those irradiated by 0 and 2 Gy, while the Cat and NF-kappaB expressions were fairly stable. A systems biology model was developed to shed more light on how MnSOD affects the biological state of cells depending upon the production of H2O2. By raising the initial presence of MnSOD in the 0.7-10 x 10-6 M concentration range, the nuclear NF-kappaB (NF-kappaBn)-H2O2 interplay was elucidated. Both the time-dependent and steady-state concentrations of H2O2 for various initial levels of MnSOD were contrasted. The systems biology model has been compared with our experimental data suggesting that, in the absence of Cat, the expression enhancements of MnSOD and CuZnSOD may form a positive feed-forward relation with the antiapoptotic NF-kappaB gene regulator, which leads to a relatively successful PC-3 cell adaptation to prooxidative conditions induced by IR. In this light our systems biology model indicates that a possible mechanism for the adaptation of prostate cancer cells to IR is assocciated with a decreasing trend of effective concentrations of H2O2 due to MnSOD induction. It is believed that our results provide a systems biology framework supporting several experimental hypotheses upon which a promising therapeutic strategy of metastatic prostate cancer should rely. |
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Frontiers in Chemical Biology
5:00 PM-7:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Biological Chemistry |