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Thermotolerance, the acquired resistance of cells to stress, is a well-established phenomenon. Studies of the key mediators of this response, the heat shock proteins (HSPs), have led to the discovery of the important roles played by these proteins in the regulation of apoptotic cell death. Apoptosis is critical for normal tissue homeostasis and is involved in diverse processes including development and immune clearance. Apoptosis is tightly regulated by both proapoptotic and antiapoptotic factors, and dysregulation of apoptosis plays a significant role in the pathophysiology of many diseases. In the recent years, HSPs have been identified as key determinants of cell survival, which can modulate apoptosis by directly interacting with components of the apoptotic machinery. Therefore, manipulation of the HSPs could represent a viable strategy for the treatment of diseases. Here, we review the current knowledge with regard to the mechanisms of HSP-mediated regulation of apoptosis.
In 2018, in the US alone, it is estimated that 268,670 people will be diagnosed with breast cancer, and that 41,400 will die from it. Since breast cancers often become resistant to therapies, and certain breast cancers lack therapeutic targets, new approaches are urgently required. A cell-stress response pathway, the unfolded protein response (UPR), has emerged as a promising target for the development of novel breast cancer treatments. This pathway is activated in response to a disturbance in endoplasmic reticulum (ER) homeostasis but has diverse physiological and disease-specific functions. In breast cancer, UPR signalling promotes a malignant phenotype and can confer tumours with resistance to widely used therapies. Here, we review several roles for UPR signalling in breast cancer, highlighting UPR-mediated therapy resistance and the potential for targeting the UPR alone or in combination with existing therapies.
Proteins destined for the secretory pathway are processed in the endoplasmic reticulum (ER) where a delicate balance exists between protein folding and degradation of terminally misfolded proteins. Different physiological as well as pathological stress conditions however, can lead to an imbalance between the ER protein folding capacity and protein load, giving rise to an accumulation of misfolded proteins in the ER lumen, a condition dubbed as ‘ER stress’. In an attempt to meet the increased folding demand, cells utilize a conserved signaling pathway, the unfolded protein response (UPR), which is initially charged to re-establish ER homeostasis and support survival. If this mechanism fails, persistent ER stress will eventually cause this cytoprotective UPR to switch into a cell death pathway that can activate mitochondrial apoptosis. As such, the dual function of the UPR in controlling cell fate may play a part in disease development and response to stress signals in conflicting ways. The lethal arm of the UPR may contribute to pathologies that are linked to unscheduled cell death, like diabetes and certain neurodegenerative diseases such as Alzheimer's and Parkinson’s, or be utilized by certain anticancer drugs to kill cancer cells. On the other hand, activation of the pro-survival function of the UPR may assist processes like tumorigenesis and chemoresistance, by endowing cancer cells with an increased capability to adapt to their hostile environment and to cope with cellular damage. Therefore, a better understanding of the different signaling pathways that emanate from the stressed ER and how their integration modulates cell fate decisions represents a crucial requirement to develop new strategies aimed at targeting the UPR for therapeutic purposes.
