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Hyperthermia is a promising anticancer treatment used in combination with radiotherapy and/or chemotherapy. It uses heat (>42°C) to kill cancer cells. However, lower temperatures (39-41°C) induce thermotolerance, an adaptive survival response (hormesis) that could interfere with toxicity of cancer treatments. Exposure to low doses of stress (e.g. heat shock, reactive oxygen species (ROS)) can upregulate cellular defenses such as heat shock proteins, antioxidants and anti-apoptosis proteins, which protect cells against subsequent exposure to toxic stressors. Although hyperthermia has proven effective in clinical trials, there are still many things to learn about its cellular and molecular mechanisms. This study examines the role of ROS and antioxidants in cellular stress responses to mild (40°C) and lethal (42-43°C) hyperthermia. Hyperthermia (42-43°C) caused apoptosis and activation of caspases 9 and 3, which were decreased in thermotolerant (40°C) cancer cells. Mild and lethal hyperthermia both increased ROS levels in cells, relative to 37°C. Exposure to mild and lethal hyperthermia increased protein expression of the antioxidants peroxiredoxin-2 (Prx2) and Prx3. Expression of the hyperoxidized form Prx-SO3 increased only at higher temperatures (>42°C). The increases in Prx3 and Prx-SO3 levels at 42°C were inhibited by the antioxidants PEG-catalase and MnTBAP. In thermotolerant (40°C) cells, transcription factor Nrf2 was upregulated. The heat–induced increase in Prx3 expression was diminished in shRNA Nrf2 cells. Furthermore, heat (40-43°C) increased levels of reduced glutathione (GSH), which were inhibited by PEG-catalase and MnTBAP. These results suggest that heat-induced ROS were involved in the induction of antioxidants and shed some light on the role of antioxidants in cellular responses induced by heat shock at both mild and lethal temperatures. Improved knowledge about induction of adaptive survival responses by low-dose heat shock could have potential to protect against toxicity of multiple xenobiotics. |
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