CHOP Is Involved in Endoplasmic Reticulum Stress-induced Apoptosis by Enhancing DR5 Expression in Human Carcinoma Cells*

By H. Yamaguchi, Hong-Gang Wang. Journal of Biological Chemistry, 2004

828 citations recorded by the source corpus.

It has been shown that excess stress to the endoplasmic reticulum (ER) triggers apoptosis, but the mechanisms underlying these processes remain unclear. We and others have reported previously that DR5 expression is up-regulated in thapsigargin (THG)-treated human cancer cells. Here, we provide evidence that CHOP is involved in THG up-regulation of DR5, which is a critical step for ER stress-induced apoptosis in human cancer cells. In human colon cancer HCT116 cells, knockdown of DR5 by siRNA blocked THG-induced Bax conformational change along with caspase-3 activation and cell death. Moreover, inhibition of CHOP expression attenuated DR5 up-regulation and apoptosis induced by THG, whereas ectopic expression of DR5 restored the sensitivity of CHOP siRNA-transfected cells to THG-induced apoptosis. In addition to HCT116 cells, inhibition of CHOP or DR5 induction also attenuated THG-induced cell death in other cancer cell lines including LNCaP, A2780S, and DU145, indicating that CHOP and DR5 are critical for ER stress-mediated apoptosis in human carcinoma cells. Furthermore, we identified a potential CHOP-binding site in the 5′-flanking region of the DR5 gene. Mutation of this site abrogated the enhanced reporter activity in response to THG treatment. Together, our findings suggest that CHOP regulates ER stress-induced apoptosis, at least in part, through enhancing DR5 expression in some types of human cancer cells.

Subfields: Cell Biology, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e0050e14b635735d53e1a06a11e139288e8c7a3f

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Citations in the corpus

Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis. (2008, background): “Moreover, ER stress has been shown to induce expression of death receptor (143), potentially invoking the extrinsic pathway of apoptosis so that in reality, both classical pathways of apoptosis will likely be active once cell membranes have been disrupted.”
The impact of the unfolded protein response on human disease (2012, neutral): “CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells.”
Endoplasmic Reticulum Stress in Liver Disease (2010, background): “CHOP can transcriptionally up regulate the expression of the death receptor TRAIL receptor 2 (also known as death receptor 5, DR5) in human cancer cell lines [148].”
The role for endoplasmic reticulum stress in diabetes mellitus. (2008, background): “and sensitization to a subsequent oxidative stress (139); 3) up-regulation of the death receptor 5 (140) and of Bim (141) (see below); and 4) induction of TRB3, an Akt inhibitor shown to contribute to ER stress-mediated death (142).”
Adaptation to ER Stress Is Mediated by Differential Stabilities of Pro-Survival and Pro-Apoptotic mRNAs and Proteins (2006, background): “It has also been proposed that CHOP leads to transcriptional repression of the antiapoptotic BCL-2 protein [45], and to up-regulation of the death receptor family member DR5 [46].”
The endoplasmic reticulum and the unfolded protein response. (2007, background): “DR5 encodes a cell surface death receptor that may activate caspase cascades [64].”
Lipotoxicity and the gut-liver axis in NASH pathogenesis. (2018, background): “CHOP and by JNK during ER stress [39, 51] and is considered a major mediator of lipotoxicity [50].”
The eIF2α kinases: their structures and functions (2013, neutral): “The first is regulation of genes involved in apoptotic pathways, such as the Bcl-2 family members BCL-2 and BIM, and the death receptor DR5 [127, 156, 202].”
Endoplasmic Reticulum Stress and Oxidative Stress: A Vicious Cycle or a Double-Edged Sword? (2007, neutral): “Dr5 encodes a cell-surface death receptor that may activate caspase cascades (153).”
Cellular response to endoplasmic reticulum stress: a matter of life or death (2006, background): “transcriptionally downregulate the antiapoptotic protein Bcl2(135) and upregulate DR5, a member of the death receptor protein family.(136,137) Interestingly, CHOP also leads to a depletion of cellular glutathione and an increase in ROS in Adaptive and apoptotic responses to ER stress M Boyce and J Y”
ER stress-induced cell death mechanisms. (2013, background): “In addition, p38 MAPK phosphorylates and activates the transcription factor CHOP, which causes changes in gene expression that favor apoptosis, including increasing expression of Bim and DR5, while decreasing expression of Bcl-2 [8,9].”