Signal transduction in ER stress: the role of the 'Unfolded protein response' in anticancer therapy.

The endoplasmic reticulum (ER) is both a major intracellular calcium store and the place where proteins of the secretory pathway are synthesized, folded, modified and delivered to their final cell surface or extracellular destination. Disturbance in any of these functions, which results in the disruption of the proper folding and secretory capacity of the ER and increased load of unfolded proteins in its lumen, defines a condition known as ER stress. ER stress is set off by various intracellular and extracellular perturbations, including glucose deprivation, redox unbalance and depletion of the ER Ca2+ store, which alter the protein folding capacity of the ER. Following perturbation in ER homeostasis a complex signal transduction cascade, called the unfolded protein response (UPR) is initiated in order to restore normal ER homeostasis. However, when these mechanisms fail to restore normal ER homeostasis, ER stress promotes the cell death program, which is usually in the form of apoptosis. UPR is an emerging stress-mediated response with putative role in carcinogenesis and in therapy resistance. Therefore, the overall goal of the current project is to define the functional relevance of the ER stress response activated by cytotoxic drugs and its role in modulating the therapeutic outcome. Towards this end, we will endeavor studies at the intracellular, intercellular and organism levels, which are specifically focused on: i) identification of the unique and shared signaling pathways underlying the ER stress response by anticancer drugs, ii) identification of the molecular effectors linking ER stress to cell death and survival, iii) evaluation of the role of the ER stress response following anticancer treatment in vivo.

Keywords:Signal transduction

Disciplines:Morphological sciences, Oncology, Biochemistry and metabolism, Medical biochemistry and metabolism