ArticleCell death & disease2022
cFLIP downregulation is an early event required for endoplasmic reticulum stress-induced apoptosis in tumor cells.
Article in Cell death & disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 20 citations in OpenAlex.
- Neuroprotective role of NRF2 activation against ER Stress-Mediated apoptosis in obstructive sleep apnea.The Journal of biological chemistry · 2026Article
- c-FLIP as a master regulator of immune homeostasis and disease mechanisms.Cell death & disease · 2026Review
- REDD1/DDIT4 counteracts endoplasmic reticulum stress-induced apoptosis by controlling the expression of death receptor TRAILR2/DR5 in cancer cells.Cell death & disease · 2026Article
- Article
- Nuclear respiratory factor-1 promotes CFLAR transcription in H9C2 cardiomyocytes, protecting them against hypoxia-induced apoptosis.Molecular biology reports · 2025Article
- Regulation of ER stress-induced apoptotic and inflammatory responses via YAP/TAZ-mediated control of the TRAIL-R2/DR5 signaling pathway.Cell death discovery · 2025Article
- Biological Functions and Clinical Implications of CFLAR: From Cell Death Mechanisms to Therapeutic Targeting in Immune Regulation.Journal of inflammation research · 2025Review
- Endoplasmic reticulum stress-a key guardian in cancer.Cell death discovery · 2024Review
- Targeting the organelle for radiosensitization in cancer radiotherapy.Asian journal of pharmaceutical sciences · 2024Review
- Article
- Shikonin Induces ROS-Dependent Apoptosis Via Mitochondria Depolarization and ER Stress in Adult T Cell Leukemia/Lymphoma.Antioxidants (Basel, Switzerland) · 2023Article
- Endogenous PTEN acts as the key determinant for mTOR inhibitor sensitivity by inducing the stress-sensitized PTEN-mediated death axis in KSHV-associated malignant cells.Frontiers in molecular biosciences · 2023Article
- Dapagliflozin induces apoptosis by downregulating cFILPOncology letters · 2022Article
- Restoring TRAILR2/DR5-Mediated Activation of Apoptosis upon Endoplasmic Reticulum Stress as a Therapeutic Strategy in Cancer.International journal of molecular sciences · 2022Review
- Genistein Sensitizes Human Cholangiocarcinoma Cell Lines to Be Susceptible to Natural Killer Cells.Biology · 2022Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protein misfolding or unfolding and the resulting endoplasmic reticulum (ER) stress frequently occur in highly proliferative tumors. How tumor cells escape cell death by apoptosis after chronic ER stress remains poorly understood. We have investigated in both two-dimensional (2D) cultures and multicellular tumor spheroids (MCTSs) the role of caspase-8 inhibitor cFLIP as a regulator of the balance between apoptosis and survival in colon cancer cells undergoing ER stress. We report that downregulation of cFLIP proteins levels is an early event upon treatment of 2D cultures of colon cancer cells with ER stress inducers, preceding TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) upregulation, caspase-8 activation, and apoptosis. Maintaining high cFLIP levels during ER stress by ectopic expression of cFLIP markedly inhibits ER stress-induced caspase-8 activation and apoptosis. Conversely, cFLIP knockdown by RNA interference significantly accelerates caspase-8 activation and apoptosis upon ER stress. Despite activation of the proapoptotic PERK branch of the unfolded protein response (UPR) and upregulation of TRAIL-R2, MCTSs are markedly more resistant to ER stress than 2D cultures of tumor cells. Resistance of MCTSs to ER stress-induced apoptosis correlates with sustained cFLIP
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