Review. The endoplasmic reticulum: a target for new anticancer drugs.

In eukaryotic cells, the endoplasmic reticulum (ER) is the principal site for the folding and maturation of transmembrane, secretory and ER-resident proteins. Functions of the ER are affected by various intracellular and extracellular stimuli, which include inhibition of glycosylation, reduction of disulfide bonds, calcium depletion from the ER lumen, impairment of protein transport to the Golgi, and expression of mutated proteins in the ER. Under ER stress, unfolded/misfolded proteins accumulate in the ER lumen, which induces conflicting cellular activities: survival and apoptosis. To cope with this stress, cells activate intracellular signalling pathways, such as the unfolded protein response (UPR) and the ER-associated degradation (ERAD). However, under conditions of severe ER stress or when the UPR has been compromised, the cell may be incapable of maintaining ER homeostasis, which may eventually activate programmed cell death (PCD) pathways. Clinical data support the potential of drugs that inhibit the normal functions and homeostasis of the ER and the proteasome in treatment of malignancies like cancer. It is therefore reasonable to assume that manipulation of ER stress might enhance the efficacy of chemotherapeutic drugs and provide new anticancer targets like the ER and the proteasome.