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

Elodie Lafont

doi:10.3390/cancers12051113

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.

Highlights

Death Receptors (DRs) are a clade of transmembrane proteins belonging to the Tumour NecrosisFactor Receptor Super Family (TNFRSF)
DRs comprise the broadly studied TNFR1, CD95/Fas/APO-1, TNF-Related Apoptosis-Inducing Ligand-Receptor 1 (TRAIL-R1)/DR4, and TRAIL-R2/DR5, on which we focus here
The Strasser’s laboratory demonstrated early on that Bim is required for Endoplasmic Reticulum (ER)-stress-induced cell death in multiple cell lines and highlighted that ER stress activates Bim through Protein Phosphatase 2A (PP2A)-mediated dephosphorylation, preventing Bim degradative ubiquitination; and through CHOP-dependent which promotes the expression of various genes, including Bim [234], TRAIL-R2, and represses other, contributing to death induction

Summary

Introduction

Death Receptors (DRs) are a clade of transmembrane proteins belonging to the Tumour Necrosis. TNFR1, CD95 and TRAIL-R1/2 were initially shown to trigger cell death, including apoptosis, which involves caspase activation and is referred to as the extrinsic apoptotic pathway. Smac Mimetics (SM) [79,80,81] In addition to their direct role in TNFR1 signalling, cIAPs constitutively limit non-canonical NF-κB activation and ensuing production of cytokines (including TNF itself). The requirement of RIPK1 in TRAIL- and CD95L-induced gene-activation signalling seems to depend on the cell-type [176,178,179,181]. Tumours to select those that could benefit from TRAIL-R-targeting therapies and propose efficient combination therapies to circumvent resistance and (ii) understanding the pro-oncogenic role of TRAIL-R, including its impact on the cross-talk between tumour and stromal cells, and (iii) identifying markers (like KRas mutation) determining whether a TRAIL-R-blocking or-activating strategy would be beneficial. The UPR contributes to tumorigenesis and to chemoresistance (for recent reviews: [12,13,14,15])

Main Actors of the Unfolded Protein Response

Cross-Talk between the UPR and DR Signalling

Focus onProtein the Protein

Focus on the Enzyme-1

Conclusions