![]() While this activity resides in the RER, lipids to be delivered to other intracellular organelles are synthesized in the SER. ![]() It is also responsible for the correct folding and posttranslational modification of proteins destined to other organelles, the plasma membrane, as well as the extracellular compartment. The ER is deputed to several different activities, including calcium storage, detoxification of chemical compounds, and lipid synthesis. The extension/size of this organelle depends of cell’s activity and type (discussed later) and is organized in subdomains of different shapes such as tubules and cisternae, giving rise to two main dynamic and interconvertible structures: the smooth endoplasmic reticulum (SER) and the rough endoplasmic reticulum (RER), with membranes of the latter being decorated by ribosomes transiently attached to the external side ( 1). It is immediately adjacent to the cell nucleus its membrane is continuous with the outer membrane of the nuclear envelope and is characterized by an extremely expanded membrane delimiting an intra-organelle space named ER lumen. The endoplasmic reticulum (hereafter ER) is the widest intracellular organelle spanning from the nuclear envelope to the cell membrane. ![]() In this review, we discuss the role played by the UPR program in tumor initiation, progression and resistance to therapy, highlighting the recent advances that have improved our understanding of the molecular mechanisms that regulate the survival/death switch. Therefore, understanding the mechanism(s) regulating the cell survival/death decision under ER stress condition may be crucial in order to specifically target tumor cells and possibly circumvent or overcome tumor resistance to therapies. However, although the UPR program is primarily a pro-survival process, sustained and/or prolonged stress may result in cell death induction. Several UPR components are in fact deregulated in different tumor types, and accumulating data indicate their active involvement in tumor development/progression. Therefore, it is not surprising that ER stress is usually induced during solid tumor development and stage progression, becoming an hallmark of such malignancies. Some of these stimuli are frequently observed during uncontrolled proliferation of transformed cells, resulting in tumor core formation and stage progression. Several physiological and pathological stimuli deregulate normal ER activity causing UPR activation, such as hypoxia, glucose shortage, genome instability, and cytotoxic compounds administration. Perturbation of endoplasmic reticulum (ER) homeostasis results in a stress condition termed “ER stress” determining the activation of a finely regulated program defined as unfolded protein response (UPR) and whose primary aim is to restore this organelle’s physiological activity.
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