Stress is an agonist for the induction of programmed cell death: A review

The prevailing models of stress induced Programmed Cell Death (PCD) posit that excess extracellular chemicals interact with or enter cells and disrupts cellular homeostasis. This activates signalling cascades involving the mitochondria, an increase in the steady state levels of Reactive Oxygen Species (ROS) as well as the activation of Bax and caspases. Further, the increased ROS also causes cellular damage that triggers or enhances PCD responses. The models have been modified in a number of ways, for example to include the existence of caspase and Bax independent forms of PCD. More recently, the ubiquity of ROS has also been challenged in part based on the failure of anti-oxidants to protect from diseases with increased intensity of oxidative stress. Here we focus on a number of other, often overlooked, observations regarding stress mediated responses that may further increase our mechanistic understanding of PCD. These include the concept of the "milieu intérieur" which suggests that cells actively protect themselves (adaptive homeostasis) in part by limiting entry to most extracellular chemicals. Of similar importance, stress also increases the levels of other stress inducible second messengers including ceramide, iron and calcium. This review focuses on the concept that stress is an agonist that conveys information that is transduced into the cell to activate the appropriate genetically encoded cell death and survival responses.