Targeting ER stress induced apoptosis and inflammation in cancer

Abstract 

Disturbance in the folding capacity of the endoplasmic reticulum (ER), caused by a variety of endogenous and exogenous insults, prompts a cellular stress condition known as ER stress. ER stress is initially shaped to re-establish ER homeostasis through the activation of an integrated intracellular signal transduction pathway termed as unfolded protein response (UPR). However, when ER stress is too severe or prolonged, the pro-survival function of the UPR turns into a toxic signal, which is predominantly executed by mitochondrial apoptosis. Moreover, accumulating evidence implicates ER stress pathways in the activation of various ‘classical’ inflammatory processes in and around the tumour microenvironment. In fact, ER stress pathways evoked by certain conventional or experimental anticancer modalities have been found to promote anti-tumour immunity by enhancing immunogenicity of dying cancer cells. Thus, the ER functions as an essential sensing organelle capable of coordinating stress pathways crucially involved in maintaining the cross-talk between the cancer cell’s intracellular and extracellular environment. In this review we discuss the emerging link between ER stress, cell fate decisions and immunomodulation and the potential therapeutic benefit of targeting this multifaceted signaling pathway in anticancer therapy.

Abbreviations: AP1, activator protein 1, APR, acute-phase response, ATF6, activating transcription factor 6, BFA, Brefeldin A, BiP, binding immunoglobulin protein, CHOP, C/EBP homologous protein, COX, cyclooxygenase-2, CREBH, cyclic-AMP-responsive-element-binding protein H, CRT, calreticulin, DAMP(s), Damage-associated Molecular Pattern(s), DC, dendritic cells, eIF2α, eukaryotic initiation factor 2 Alpha, ER, endoplasmic reticulum, ERAD, endoplasmic reticulum associated protein degradation, GRP, glucose-regulated protein, HSP, heat shock protein, IL, interleukin, IL-2R, interleukin 2 receptor, IRE1, inositol requiring enzyme 1, JNK, c-jun N-terminal kinases, KEAP1, kelch-like Ech associated protein 1, MAPK, mitogen-activated protein kinases, NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells, Nrf2, nuclear factor-E2-related factor 2, PDI, protein disulfide isomerases, PDT, photodynamic therapy, PERK, pancreatic ER kinase (PKR)-like ER kinase, ROS, reactive oxygen species, TLR(s), toll-like receptor(s), TNF, tumour necrosis factor, TRAF2, tumour necrosis factor (TNF)-receptor associated receptor 2, UPR, unfolded protein response, VEGF, vascular endothelial growth factor, XBP1, X-box binding protein 1

Keywords: ER stress, Unfolded protein response, Apoptosis, Cell death, Cancer, Anticancer therapy, Inflammation, Antitumor immune response