Marine drugs, 2018-03, Vol.16 (3), p.77
2018
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Details
- Autor(en) / Beteiligte
- Titel
- ATG5 Promotes Death Signaling in Response to the Cyclic Depsipeptides Coibamide A and Apratoxin A
- Ist Teil von
- Marine drugs, 2018-03, Vol.16 (3), p.77
- Ort / Verlag
- Switzerland: MDPI AG
- Erscheinungsjahr
- 2018
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Our understanding of autophagy and lysosomal function has been greatly enhanced by the discovery of natural product structures that can serve as chemical probes to reveal new patterns of signal transduction in cells. Coibamide A is a cytotoxic marine natural product that induces mTOR-independent autophagy as an adaptive stress response that precedes cell death. Autophagy-related (ATG) protein 5 (ATG5) is required for coibamide-induced autophagy but not required for coibamide-induced apoptosis. Using wild-type and autophagy-deficient mouse embryonic fibroblasts (MEFs) we demonstrate that coibamide-induced toxicity is delayed in ATG5 cells relative to ATG5 cells. Time-dependent changes in annexin V staining, membrane integrity, metabolic capacity and caspase activation indicated that MEFs with a functional autophagy pathway are more sensitive to coibamide A. This pattern could be distinguished from autophagy modulators that induce acute ER stress (thapsigargin, tunicamycin), ATP depletion (oligomycin A) or mTORC1 inhibition (rapamycin), but was shared with the Sec61 inhibitor apratoxin A. Coibamide- or apratoxin-induced cell stress was further distinguished from the action of thapsigargin by a pattern of early LC3-II accumulation in the absence of CHOP or BiP expression. Time-dependent changes in ATG5-ATG12, PARP1 and caspase-3 expression patterns were consistent with the conversion of ATG5 to a pro-death signal in response to both compounds.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1660-3397eISSN: 1660-3397DOI: 10.3390/md16030077Titel-ID: cdi_doaj_primary_oai_doaj_org_article_fe0786cabd4a4fc5a4ddfbda9d9869a5
- Format
- –
- Schlagworte
- Animals, Annexin V, Apoptosis, Apoptosis - drug effects, apratoxin A, ATP, Autophagy, Autophagy - drug effects, Autophagy-Related Protein 5 - genetics, Autophagy-Related Protein 5 - metabolism, BiP, Capacity, Caspase, Caspase-3, Cell death, Cell Line, Cells, Cellular stress response, coibamide A, Cytotoxicity, Depsipeptides - toxicity, Embryo fibroblasts, Embryos, Endoplasmic Reticulum Chaperone BiP, Endoplasmic Reticulum Stress - drug effects, ER stress, Fibroblasts, Gene Knockout Techniques, GRP78, Marine Toxins - toxicity, Metabolic rate, Mice, Modulators, Mortality, mTOR-independent autophagy, Natural products, Oligomycin, Oligomycin A, Phagocytosis, Poly(ADP-ribose) polymerase, Proteins, Rapamycin, Sec61, Signal transduction, Signal Transduction - drug effects, Signaling, Stress, Stresses, Thapsigargin, Thapsigargin - toxicity, Time dependence, TOR protein, Toxicity, Tunicamycin