ER stress-induced cell death proceeds independently of the TRAIL-R2 signaling axis in pancreatic \u03b2 cells

Cathrin Hagenlocher,Bruno Taschke,Angelika Hausser,Senait Wieske,Markus Rehm,Robin Siebert

doi:10.1038/s41420-022-00830-y

Abstract

Prolonged ER stress and the associated unfolded protein response (UPR) can trigger programmed cell death. Studies in cancer cell lines demonstrated that the intracellular accumulation of TRAIL receptor-2 (TRAIL-R2) and the subsequent activation of caspase-8 contribute significantly to apoptosis induction upon ER stress. While this might motivate therapeutic strategies that promote cancer cell death through ER stress-induced caspase-8 activation, it could also support the unwanted demise of non-cancer cells. Here, we therefore investigated if TRAIL-R2 dependent signaling towards apoptosis can be induced in pancreatic β cells, whose loss by prolonged ER stress is associated with the onset of diabetes. Interestingly, we found that elevated ER stress in these cells does not result in TRAIL-R2 transcriptional induction or elevated protein levels, and that the barely detectable expression of TRAIL-R2 is insufficient to allow TRAIL-induced apoptosis to proceed. Overall, this indicates that apoptotic cell death upon ER stress most likely proceeds independent of TRAIL-R2 in pancreatic β cells. Our findings therefore point to differences in ER stress response and death decision-making between cancer cells and pancreatic β cells and also have implications for future targeted treatment strategies that need to differentiate between ER stress susceptibility of cancer cells and pancreatic β cells.

Highlights

The endoplasmic reticulum (ER) is the major cellular compartment for protein folding and the location for initiating the transport of most membrane located and secreted proteins
We initially tested if those inducers of pathological ER stress dose dependently induce cell death and associated ER stress markers in pancreatic β cell lines
Here, we report that pancreatic β cells respond to elevated ER stress by triggering programmed cell death through the mitochondrial apoptosis pathway that is regulated by BCL-2 family members, mostly likely without engaging the TRAIL-R2 dependent signaling arm

Summary

INTRODUCTION

The endoplasmic reticulum (ER) is the major cellular compartment for protein folding and the location for initiating the transport of most membrane located and secreted proteins. Cells active in protein production include pancreatic β cells which are specialized for the production and controlled secretion of insulin in order to maintain blood glucose homeostasis [2] Due to their high secretory activities, β cells experience substantial intrinsic ER stress. Peripheral insulin resistance and chronic hyperglycemia due to a sedentary lifestyle contribute to prolonged and irresolvable ER stress in β cells This can impair insulin biosynthesis and secretion, resulting in β cell failure and manifestation of Diabetes mellitus (DM) [8]. Cancer cells that rapidly proliferate, often in unfavorable growth environments, face substantial demands for protein production and experience ER stress. This predisposes cancer cells to become sensitive to treatment strategies that intensify ER stress and thereby induce programmed cell death [9].

MATERIALS AND METHODS

RESULTS

Hagenlocher et al 4

DISCUSSION