Hagenlocher et al. published in Cell Deah Discovery

January 24, 2022

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

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

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.

 

doi: 10.1038/s41420-022-00830-y

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