Stress Management: Death Receptor Signalling and Cross-Talks with the Unfolded Protein Response in Cancer

Abstract

Throughout tumour progression, tumour cells are exposed to various intense cellular stress conditions owing to intrinsic and extrinsic cues, to which some cells are remarkably able to adapt. Death Receptor (DR) signalling and the Unfolded Protein Response (UPR) are two stress responses that both regulate a plethora of outcomes, ranging from proliferation, differentiation, migration, cytokine production to the induction of cell death. Both signallings are major modulators of physiological tissue homeostasis and their dysregulation is involved in tumorigenesis and the metastastic process. The molecular determinants of the control between the different cellular outcomes induced by DR signalling and the UPR in tumour cells and their stroma and their consequences on tumorigenesis are starting to be unravelled. Herein, I summarize the main steps of DR signalling in relation to its cellular and pathophysiological roles in cancer. I then highlight how the UPR and DR signalling control common cellular outcomes and also cross-talk, providing potential opportunities to further understand the development of malignancies.

Proteotoxic Stress and Cell Death in Cancer Cells

“…These conditions are responsible for the induction of ER stress [66][67][68][69][70]. In response to ER stress, cells activate UPR (unfolded protein response) [71,72]. This adaptive response is important for sustaining cell survival.…”

“…Through UPR, cells avoid the accumulation of misfolded proteins and restore the physiological condition of proteostasis. As explained above, UPR allows cells to survive the stress condition [64,[70][71][72][73]. UPR is governed by three sensors: PERK (protein kinase RNA-like ER kinase), IRE1 (inositol-requiring enzyme 1) and ATF6 (activating transcription factor 6) [64,74,75].…”

“…The best characterized is the eukaryotic translation initiation factor-2 alpha (eIF2α). PERK is able to phosphorylate eIF2α at serine 51 [70,71,76], thus blocking the CAP-dependent translation and diminishing ER stress [64]. Another notable substrate is NRF2 (nuclear factor erythroid-derived 2), the master regulator of redox homeostasis [77].…”

The Great Escape: The Power of Cancer Stem Cells to Evade Programmed Cell Death

“…The extrinsic and intrinsic pathways meet after the activation of caspase-8. DISC is a multiprotein complex composed of members of the death receptor family of apoptosis-inducing cellular receptors [ 77 , 78 , 79 ]. TNF binds to TNFR1 and TNFR2.…”

Proteotoxic Stress and Cell Death in Cancer Cells

“…Conditions that trigger the induction of the ER-stress [66][67][68][69][70]. In response to ER-stress, cells activate the UPR (Unfolded Protein Response) [71,72]. This adaptive response is important for sustaining cell survival.…”