Heat shock increases levels of reactive oxygen species, autophagy and apoptosis

Hyperthermia is a promising anticancer treatment used in combination with radiotherapy and chemotherapy. Temperatures above 41.5 degrees C are cytotoxic and hyperthermia treatments can target a localized area of the body that has been invaded by a tumor. However, non-lethal temperatures (39-41 degrees C) can increase cellular defenses, such as heat shock proteins. This adaptive survival response, thermotolerance, can protect cells against subsequent cytotoxic stress such as anticancer treatments and heat shock (>41.5 degrees C). Autophagy is another survival process that is activated by stress. This study aims to determine whether autophagy can be activated by heat shock at 42 degrees C, and if this response is mediated by reactive oxygen species (ROS). Autophagy was increased during shorter heating times (<60 min) at 42 degrees C in cells. Levels of acidic vesicular organelles (AVO) and autophagy proteins Beclin-1, LC3-II/LC-3I, Atg7 and Atg12-Atg5 were increased. Heat shock at 42 degrees C increased levels of ROS. Increased levels of LC3 and AVOs at 42 degrees C were inhibited by antioxidants. Therefore, increased autophagy during heat shock at 42 degrees C (<60 min) was mediated by ROS. Conversely, heat shock at 42 degrees C for longer times (1-3 h) caused apoptosis and activation of caspases in the mitochondrial, death receptor and endoplasmic reticulum (ER) pathways. Thermotolerant cells, which were developed at 40 degrees C, were resistant to activation of apoptosis at 42 degrees C. Autophagy inhibitors 3-methyladenine and bafilomycin sensitized cells to activation of apoptosis by heat shock (42 degrees C). Improved understanding of autophagy in cellular responses to heat shock could be useful for optimizing the efficacy of hyperthermia in the clinic.

Automated summary

Short-term heat shock at 42 degrees Celsius (<60 min) increased autophagy, while long-term heat shock (1-3 h) at 42 degrees Celsius led to apoptosis. Thermotolerant cells were resistant to apoptosis at 42 degrees Celsius. Autophagy inhibitors sensitized cells to apoptosis triggered by heat shock at 42 degrees Celsius.