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Coibamide A induces mTOR-independent autophagy and cell death in human glioblastoma cells.
|Title||Coibamide A induces mTOR-independent autophagy and cell death in human glioblastoma cells.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Hau AM, Greenwood JA, Löhr CV, Serrill JD, Proteau PJ, Ganley IG, McPhail KL, Ishmael JE|
|Keywords||Adaptor Proteins, Signal Transducing, Animals, Apoptosis, Apoptotic Protease-Activating Factor 1, Autophagy, Caspase 3, Cell Line, Tumor, Cytotoxins, Depsipeptides, Fibroblasts, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Mice, Microtubule-Associated Proteins, Organ Specificity, Phosphoproteins, Protein-Serine-Threonine Kinases, Ribosomal Protein S6 Kinases, Signal Transduction, TOR Serine-Threonine Kinases|
Coibamide A is an N-methyl-stabilized depsipeptide that was isolated from a marine cyanobacterium as part of an International Cooperative Biodiversity Groups (ICBG) program based in Panama. Previous testing of coibamide A in the NCI in vitro 60 cancer cell line panel revealed a potent anti-proliferative response and "COMPARE-negative" profile indicative of a unique mechanism of action. We report that coibamide A is a more potent and efficacious cytotoxin than was previously appreciated, inducing concentration- and time-dependent cytotoxicity (EC50<100 nM) in human U87-MG and SF-295 glioblastoma cells and mouse embryonic fibroblasts (MEFs). This activity was lost upon linearization of the molecule, highlighting the importance of the cyclized structure for both anti-proliferative and cytotoxic responses. We show that coibamide A induces autophagosome accumulation in human glioblastoma cell types and MEFs via an mTOR-independent mechanism; no change was observed in the phosphorylation state of ULK1 (Ser-757), p70 S6K1 (Thr-389), S6 ribosomal protein (Ser-235/236) and 4EBP-1 (Thr-37/46). Coibamide A also induces morphologically and biochemically distinct forms of cell death according to cell type. SF-295 glioblastoma cells showed caspase-3 activation and evidence of apoptotic cell death in a pattern that was also seen in wild-type and autophagy-deficient (ATG5-null) MEFs. In contrast, cell death in U87-MG glioblastoma cells was characterized by extensive cytoplasmic vacuolization and lacked clear apoptotic features. Cell death was attenuated, but still triggered, in Apaf-1-null MEFs lacking a functional mitochondria-mediated apoptotic pathway. From the study of ATG5-null MEFs we conclude that a conventional autophagy response is not required for coibamide A-induced cell death, but likely occurs in dying cells in response to treatment. Coibamide A represents a natural product scaffold with potential for the study of mTOR-independent signaling and cell death mechanisms in apoptotic-resistant cancer cells.
|Alternate Journal||PLoS ONE|