TY - JOUR
T1 - Negligible role of TRAIL death receptors in cell death upon endoplasmic reticulum stress in B-cell malignancies
AU - Favaro, Francesca
AU - Both, Demi
AU - Derks, Ingrid A. M.
AU - Spaargaren, Marcel
AU - Muñoz-Pinedo, Cristina
AU - Eldering, Eric
N1 - Funding Information: We thank for funding the EU’s H2020 Research and Innovation Programme under the Marie Skłodowska-Curie Grant Agreement 766214 (META-CAN). We thank the collaborators of this project, especially Steven Treon for the BCWM.1 cell line and master student Marleen Huijsmans who performed the studies on the BCWM.1-Bid KO cells. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Impairments in protein folding in the endoplasmic reticulum (ER) lead to a condition called ER stress, which can trigger apoptosis via the mitochondrial or the death receptor (extrinsic) pathway. There is controversy concerning involvement of the death receptor (DR)4 and DR5-Caspase-8 –Bid pathway in ER stress-mediated cell death, and this axis has not been fully studied in B-cell malignancies. Using three B-cell lines from Mantle Cell Lymphoma, Waldenström’s macroglobulinemia and Multiple Myeloma origins, we engineered a set of CRISPR KOs of key components of these cell death pathways to address this controversy. We demonstrate that DR4 and/or DR5 are essential for killing via TRAIL, however, they were dispensable for ER-stress induced-cell death, by Thapsigargin, Brefeldin A or Bortezomib, as were Caspase-8 and Bid. In contrast, the deficiency of Bax and Bak fully protected from ER stressors. Caspase-8 and Bid were cleaved upon ER-stress stimulation, but this was DR4/5 independent and rather a result of mitochondrial-induced feedback loop subsequent to Bax/Bak activation. Finally, combined activation of the ER-stress and TRAIL cell-death pathways was synergistic with putative clinical relevance for B-cell malignancies.
AB - Impairments in protein folding in the endoplasmic reticulum (ER) lead to a condition called ER stress, which can trigger apoptosis via the mitochondrial or the death receptor (extrinsic) pathway. There is controversy concerning involvement of the death receptor (DR)4 and DR5-Caspase-8 –Bid pathway in ER stress-mediated cell death, and this axis has not been fully studied in B-cell malignancies. Using three B-cell lines from Mantle Cell Lymphoma, Waldenström’s macroglobulinemia and Multiple Myeloma origins, we engineered a set of CRISPR KOs of key components of these cell death pathways to address this controversy. We demonstrate that DR4 and/or DR5 are essential for killing via TRAIL, however, they were dispensable for ER-stress induced-cell death, by Thapsigargin, Brefeldin A or Bortezomib, as were Caspase-8 and Bid. In contrast, the deficiency of Bax and Bak fully protected from ER stressors. Caspase-8 and Bid were cleaved upon ER-stress stimulation, but this was DR4/5 independent and rather a result of mitochondrial-induced feedback loop subsequent to Bax/Bak activation. Finally, combined activation of the ER-stress and TRAIL cell-death pathways was synergistic with putative clinical relevance for B-cell malignancies.
UR - http://www.scopus.com/inward/record.url?scp=85147706103&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41389-023-00450-w
DO - https://doi.org/10.1038/s41389-023-00450-w
M3 - Article
C2 - 36755015
SN - 2157-9024
VL - 12
JO - Oncogenesis
JF - Oncogenesis
IS - 1
M1 - 6
ER -