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

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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, A. M., Greenwood, J. A., Löhr, C. V., Serrill, J. D., Proteau, P. J., Ganley, I. G., . . . Ishmael, J. E. (2013). Coibamide A induces mTOR-independent autophagy and cell death in human glioblastoma cells. PloS One, 8(6), e65250. doi:10.1371/journal.pone.0065250
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  • description.provenance : Submitted by Deborah Campbell (deborah.campbell@oregonstate.edu) on 2013-08-12T21:48:45Z No. of bitstreams: 2 license_rdf: 1370 bytes, checksum: cd1af5ab51bcc7a5280cf305303530e9 (MD5) HauAndrewMPharmacyCoibamideInducesmTOR.pdf: 11264855 bytes, checksum: 14ae924b1bf63346e41bbc7bc80c35fe (MD5)
  • description.provenance : Made available in DSpace on 2013-08-12T21:49:40Z (GMT). No. of bitstreams: 2 license_rdf: 1370 bytes, checksum: cd1af5ab51bcc7a5280cf305303530e9 (MD5) HauAndrewMPharmacyCoibamideInducesmTOR.pdf: 11264855 bytes, checksum: 14ae924b1bf63346e41bbc7bc80c35fe (MD5) Previous issue date: 2013-06-06
  • description.provenance : Approved for entry into archive by Deborah Campbell(deborah.campbell@oregonstate.edu) on 2013-08-12T21:49:40Z (GMT) No. of bitstreams: 2 license_rdf: 1370 bytes, checksum: cd1af5ab51bcc7a5280cf305303530e9 (MD5) HauAndrewMPharmacyCoibamideInducesmTOR.pdf: 11264855 bytes, checksum: 14ae924b1bf63346e41bbc7bc80c35fe (MD5)

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