ReviewTargeting the endoplasmic reticulum-stress response as an anticancer strategy
Section snippets
Endoplasmic reticulum stress and the unfolded protein response: an overview
The endoplasmic reticulum (ER) comprises a complex membranous network found in all eukaryotic cells. It plays a crucial role in normal cellular functioning, particularly with regard to folding and post-translational modification of secretory proteins and membrane proteins, that are synthesized along the membrane of the rough ER and passed onto the Golgi apparatus for post-translational modifications, such as glycosylation and lipidation. In order to accomplish its protein folding functions the
Therapeutic targeting of ER stress pathways: an overview
The cellular response to ER stress is currently understood to elicit partially overlapping and conflicting signals. On the one hand it induces cytoprotective functions by activating signaling pathways to reestablish cellular homeostasis, while on the other hand, if the stress is prolonged and unresolved, then signaling pathways that promote apoptosis are activated. The current hypothesis is that the protective functions provide a window for the cell to resolve the stress and reestablish
State of the art: drugs currently in development affecting ER stress pathways
There are a number of drugs under development that affect one or more of the branches of the unfolded protein response (Table 2), although a drug discovery effort aimed at specifically inhibiting the unfolded protein response is, to our knowledge still lacking. However, there are a few grant applications that have been funded to investigate this approach (http://www.cancerportfolio.org). Below we have outlined different compounds that affect the unfolded protein response although it may not be
Future perspectives and remaining questions
Due to the demands made on cells by the malignant process, the induction of the ER stress pathway is likely to be an important contributor to tumor survival and growth, and an activated stress response may also be a key driver in the development of resistance to chemotherapeutic agents. One of the major challenges for cancer therapy is finding a therapeutic window where it is possible to selectively kill cancer cells without harming normal cells. The activation of the unfolded protein response
Acknowledgements
Our work on ER stress is supported by grants from Science Foundation Ireland (05/IN3/B851) and Enterprise Ireland.
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