Coibamide A induces mTOR-independent autophagy and cell death in human glioblastoma cells
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-prolifera...
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| Veröffentlicht in: | PloS one 2013-06, Vol.8 (6), p.e65250 |
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| creator | Hau, Andrew M Greenwood, Jeffrey A Löhr, Christiane V Serrill, Jeffrey D Proteau, Philip J Ganley, Ian G McPhail, Kerry L Ishmael, Jane E |
| description | 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 |
| doi_str_mv | 10.1371/journal.pone.0065250 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0065250</identifier><identifier>PMID: 23762328</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - metabolism ; Animals ; Apaf-1 protein ; Apoptosis ; Apoptosis - drug effects ; Apoptotic Protease-Activating Factor 1 - deficiency ; Apoptotic Protease-Activating Factor 1 - genetics ; Autophagy ; Autophagy - drug effects ; Autophagy-Related Protein 5 ; Autophagy-Related Protein-1 Homolog ; Bioaccumulation ; Biochemistry ; Biodiversity ; Biology ; Brain cancer ; Cancer ; Caspase ; Caspase 3 - genetics ; Caspase 3 - metabolism ; Caspase-3 ; Cell cycle ; Cell Cycle Proteins ; Cell death ; Cell Line, Tumor ; Cyanobacteria ; Cytotoxicity ; Cytotoxins - pharmacology ; Depsipeptides - pharmacology ; Embryo fibroblasts ; Fibroblasts ; Fibroblasts - cytology ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Gene Expression Regulation, Neoplastic - drug effects ; Glioblastoma ; Glioblastoma cells ; Glioblastomas ; Glioma ; Growth factors ; Humans ; Immunoglobulins ; Intracellular Signaling Peptides and Proteins - genetics ; Intracellular Signaling Peptides and Proteins - metabolism ; Kinases ; Mathematics ; Medical prognosis ; Medicine ; Melanoma ; Mice ; Microtubule-Associated Proteins - deficiency ; Microtubule-Associated Proteins - genetics ; Mitochondria ; Mortality ; Natural products ; Organ Specificity ; Phagocytosis ; Pharmaceutical sciences ; Phosphoproteins - genetics ; Phosphoproteins - metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases - genetics ; Protein Serine-Threonine Kinases - metabolism ; Proteins ; Ribosomal Protein S6 Kinases - genetics ; Ribosomal Protein S6 Kinases - metabolism ; Signal Transduction - drug effects ; Signaling ; TOR protein ; TOR Serine-Threonine Kinases - genetics ; TOR Serine-Threonine Kinases - metabolism ; Toxicity</subject><ispartof>PloS one, 2013-06, Vol.8 (6), p.e65250</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Hau et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Hau et al 2013 Hau et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-5bd3f7eda75439afa7b209f98c389f86d18b21c1dafe9de47ac1aebc5e809cf23</citedby><cites>FETCH-LOGICAL-c692t-5bd3f7eda75439afa7b209f98c389f86d18b21c1dafe9de47ac1aebc5e809cf23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675158/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675158/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23865,27923,27924,53790,53792,79371,79372</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23762328$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ko, Ben C.B.</contributor><creatorcontrib>Hau, Andrew M</creatorcontrib><creatorcontrib>Greenwood, Jeffrey A</creatorcontrib><creatorcontrib>Löhr, Christiane V</creatorcontrib><creatorcontrib>Serrill, Jeffrey D</creatorcontrib><creatorcontrib>Proteau, Philip J</creatorcontrib><creatorcontrib>Ganley, Ian G</creatorcontrib><creatorcontrib>McPhail, Kerry L</creatorcontrib><creatorcontrib>Ishmael, Jane E</creatorcontrib><title>Coibamide A induces mTOR-independent autophagy and cell death in human glioblastoma cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Animals</subject><subject>Apaf-1 protein</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptotic Protease-Activating Factor 1 - deficiency</subject><subject>Apoptotic Protease-Activating Factor 1 - genetics</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Autophagy-Related Protein 5</subject><subject>Autophagy-Related Protein-1 Homolog</subject><subject>Bioaccumulation</subject><subject>Biochemistry</subject><subject>Biodiversity</subject><subject>Biology</subject><subject>Brain cancer</subject><subject>Cancer</subject><subject>Caspase</subject><subject>Caspase 3 - genetics</subject><subject>Caspase 3 - 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23762328</pmid><doi>10.1371/journal.pone.0065250</doi><tpages>e65250</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-06, Vol.8 (6), p.e65250 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1365653274 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Animals Apaf-1 protein Apoptosis Apoptosis - drug effects Apoptotic Protease-Activating Factor 1 - deficiency Apoptotic Protease-Activating Factor 1 - genetics Autophagy Autophagy - drug effects Autophagy-Related Protein 5 Autophagy-Related Protein-1 Homolog Bioaccumulation Biochemistry Biodiversity Biology Brain cancer Cancer Caspase Caspase 3 - genetics Caspase 3 - metabolism Caspase-3 Cell cycle Cell Cycle Proteins Cell death Cell Line, Tumor Cyanobacteria Cytotoxicity Cytotoxins - pharmacology Depsipeptides - pharmacology Embryo fibroblasts Fibroblasts Fibroblasts - cytology Fibroblasts - drug effects Fibroblasts - metabolism Gene Expression Regulation, Neoplastic - drug effects Glioblastoma Glioblastoma cells Glioblastomas Glioma Growth factors Humans Immunoglobulins Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism Kinases Mathematics Medical prognosis Medicine Melanoma Mice Microtubule-Associated Proteins - deficiency Microtubule-Associated Proteins - genetics Mitochondria Mortality Natural products Organ Specificity Phagocytosis Pharmaceutical sciences Phosphoproteins - genetics Phosphoproteins - metabolism Phosphorylation Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Proteins Ribosomal Protein S6 Kinases - genetics Ribosomal Protein S6 Kinases - metabolism Signal Transduction - drug effects Signaling TOR protein TOR Serine-Threonine Kinases - genetics TOR Serine-Threonine Kinases - metabolism Toxicity |
| title | Coibamide A induces mTOR-independent autophagy and cell death in human glioblastoma cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-11T19%3A10%3A16IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Coibamide%20A%20induces%20mTOR-independent%20autophagy%20and%20cell%20death%20in%20human%20glioblastoma%20cells&rft.jtitle=PloS%20one&rft.au=Hau,%20Andrew%20M&rft.date=2013-06-06&rft.volume=8&rft.issue=6&rft.spage=e65250&rft.pages=e65250-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0065250&rft_dat=%3Cgale_plos_%3EA478411180%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1365653274&rft_id=info:pmid/23762328&rft_galeid=A478411180&rft_doaj_id=oai_doaj_org_article_ad6d170e6dbe49d98aa2c9990206bcf2&rfr_iscdi=true |