Endoplasmic Reticulum Stress in Cancers

Cellular homeostasis is supported by a symphonic balancing act involving protein synthesis, folding, modification, trafficking and degradation. In eukaryotic cells the endoplasmic reticulum (ER) is a specialized organelle that is the central site of synthesis and folding of secretory, membrane and a number of organelletargeted proteins. Correct folding and post-translational modifications of these proteins are enabled by the presence of ATP, Ca++, molecular chaperone proteins, and an oxidizing environment that promotes disulphide bond formation [1]. Properly folded proteins are efficiently exported to the Golgi apparatus and other intracellular organelles, while misfolded proteins are recognized by ER quality control machinery (ERQC), translocated to the cytoplasm and targeted for degradation by the ER-associated degradation (ERAD) ubiquitin-proteosome system [2,3]. A hypothesized 30% of newly synthesized, potentially misfolded proteins are targeted for degradation under normal cellular physiology [4]. Given this surprising preexisting burden, even acute perturbations in the ER lumen environment and/or cellular events that disrupt chaperone activity may result in the severe accumulation and aggregation of unfolded or misfolded proteins. Protein Disulfide Isomerase Superfamily in Disease and the Regulation of Apoptosis