Fold up or perish: unfolded protein response and chemotherapy

The acquisition of the endoplasmic reticulum (ER) during evolution of eukaryotes represents one of the fundamental shifts in biochemical reactions, from the relics of prokaryotes in which biochemical processes occur in the cytosol, requiring the primordial, anaerobic reducing conditions, to the far more sophisticated metabolic pathways in which oxygen is an absolute necessity. In eukaryotes, the ER is recognised as the site of synthesis and folding of secreted, membrane-bound and some organelle-targeted proteins. Several factors are required for disulphide-bond formation, which is needed for optimal protein folding, including ATP, Ca²⁺ and an oxidising environment.¹ As a consequence of these special requirements, the ER is highly sensitive to stresses that perturb cellular energy levels, the redox state or Ca²⁺ concentration. Such stresses reduce the protein-folding capacity of the ER, which can result in the accumulation and aggregation of unfolded proteins and/or an imbalance between the load of resident and transit proteins in the ER and the organelle's ability to process that load. This condition is referred to as ER stress. The ER stress response can promote cellular repair and sustained survival by reducing the load of unfolded proteins through global attenuation of protein synthesis and/or upregulation of chaperones, enzymes and structural components of the ER, which enhance protein folding.² This response is collectively termed as the unfolded protein response (UPR) and it is mediated through three ER transmembrane receptors: pancreatic ER kinase (PERK), activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE1). In resting cells, all of these ER stress receptors are maintained in an inactive state through their association with the ER chaperone, GRP78 (also called BiP). Accumulation of unfolded proteins causes dissociation of GRP78 from PERK, ATF6 and IRE1, thereby initiating the UPR. Thus, the UPR is a pro-survival response to reduce the accumulation of unfolded proteins and restore normal ER function.³ In addition, the UPR plays a critical role in certain developmental processes that are associated with increased demand for protein synthesis and/or export, such as differentiation of immunoglobulin (Ig)-secreting plasma cells and myoblast formation.^{4, 5} However, when misfolded-protein aggregation persists and the ER stress cannot be resolved, signalling switches from a pro-survival to a pro-apoptotic response. Thus lack of a UPR could be a mortal danger but an excessive response could be an absolute disaster!

Endoplasmic reticulum-associated degradation (also called ERAD) is an integral part of the ER quality assurance system and directs misfolded proteins for destruction by the cytoplasmic ubiquitin–proteasome pathway.⁶ The ERAD activity depends on the functions of the UPR; notably, several components of the ERAD system are under transcriptional control of the UPR.⁷ Thus, there is a regulatory loop connecting the ERAD with the UPR. Furthermore, since ERAD depends on the cytoplasmic protein degradation machinery, it appears likely that the UPR also depends on the proteasome machinery. The connection between UPR and cancer was first demonstrated in 1996 when it was reported that the major ER chaperone GRP78/BiP was highly induced in many tumours and molecular inhibition of this induction in the fibrosarcoma B/C10ME, while not affecting in vitro cellular proliferation, caused a dramatic increase in apoptotic cell death through ER stress and tumour regression in vivo.⁸ Similarly, Romero-Ramirez et al.⁹ had reported that XBP-1, the transcription factor involved in UPR, is essential for sustained tumour cell survival and cancer growth. Finally, it was shown that PERK-expressing tumours grow more rapidly than PERK-negative tumours in nude mice.¹⁰ Thus chemotherapeutic drug targeting of the UPR machinery offers a potential strategy for treating various forms of cancer. Indeed, this is reflected in several published studies on the mechanisms of action of chemotherapeutic drugs that target the protein degradation machinery.

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