Coibamide A Induces mTOR-Independent Autophagy and Cell Death in Human Glioblastoma Cells

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  • 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.
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  • Hau AM, Greenwood JA, Löhr CV, Serrill JD, Proteau PJ, Ganley IG, et al. (2013) Coibamide A Induces mTOR-Independent Autophagy and Cell Death in Human Glioblastoma Cells. PLoS ONE 8(6): e65250.
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  • 8
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  • 6
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  • Financial support was provided by: the NIH Fogarty International Center ICBG grant TW006634-06, the Medical Research Foundation of Oregon, the American Foundation for Pharmaceutical Education and the OSU College of Pharmacy and Division of Health Sciences. We are also grateful for services provided by the Cell Imaging and Analysis Facilities and Services Core of the OSU Environmental Health Sciences Center (NIEHS grant P30-ES000210).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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