Secretory stressors induce intracellular death receptor accumulation to control apoptosis.
| Title: | Secretory stressors induce intracellular death receptor accumulation to control apoptosis. |
|---|---|
| Authors: | van Raam BJ; Metabolism and Signaling in Cancer, BioMed X Innovation Center, Im Neuenheimer Feld 583, Heidelberg 69120, Germany.; Lacina T; Metabolism and Signaling in Cancer, BioMed X Innovation Center, Im Neuenheimer Feld 583, Heidelberg 69120, Germany.; Lindemann RK; Merck Serono TA Oncology, Merck KGaA, Frankfurter Str. 250, Darmstadt D-64293, Germany.; Reiling JH; Metabolism and Signaling in Cancer, BioMed X Innovation Center, Im Neuenheimer Feld 583, Heidelberg 69120, Germany. |
| Source: | Cell death & disease [Cell Death Dis] 2017 Oct 05; Vol. 8 (10), pp. e3069. Date of Electronic Publication: 2017 Oct 05. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: London : Nature Pub. Group |
| MeSH Terms: | Endoplasmic Reticulum Stress/*drug effects ; Neoplasms/*drug therapy ; Receptors, TNF-Related Apoptosis-Inducing Ligand/*genetics; Apoptosis/drug effects ; CASP8 and FADD-Like Apoptosis Regulating Protein/genetics ; Caspase 8/genetics ; Endoplasmic Reticulum Stress/genetics ; Golgi Apparatus/drug effects ; Golgi Apparatus/genetics ; Neoplasms/genetics ; Neoplasms/pathology ; Cell Line, Tumor ; Humans |
| Abstract: | Disruption of the Golgi apparatus can induce a distinct form of programmed cell death that has not been thoroughly characterized. We found that pharmacological application of Golgi stress leads to induction of death receptors (DRs) 4 and 5. DR4 appears to be primarily responsible for the initiation of cell death downstream of Golgi stress, whereas DR5 seems to be more important for cell death triggered by endoplasmic reticulum (ER) stress in specific cancer cell lines. DR induction downstream of either Golgi or ER stress mainly causes intracellular accumulation of DR4 presumably at the Golgi, rather than increased expression on the cell surface. Nevertheless, cells treated with secretory pathway stressors displayed an increased susceptibility to TRAIL (tumor necrosis factor related apoptosis inducing ligand), the endogenous ligand of DR4/5, probably due to intracellular sequestration of the caspase-8 regulator CFLAR (caspase-8 and FADD-like apoptosis regulator). These findings have implications for the treatment of cancer with DR agonists and our general understanding of DR signaling while highlighting the role of the Golgi apparatus as a cell death signaling platform. |
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| Substance Nomenclature: | 0 (CASP8 and FADD-Like Apoptosis Regulating Protein); 0 (CFLAR protein, human); 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand); 0 (TNFRSF10A protein, human); 0 (TNFRSF10B protein, human); EC 3.4.22.- (Caspase 8) |
| Entry Date(s): | Date Created: 20171006 Date Completed: 20180608 Latest Revision: 20181113 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC5680588 |
| DOI: | 10.1038/cddis.2017.466 |
| PMID: | 28981087 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't