ASC Induces Apoptosis via Activation of Caspase-9 by Enhancing Gap Junction-Mediated Intercellular Communication
ASC (apoptosis-associated speck-like protein containing a CARD) is a key adaptor molecule of inflammasomes that mediates inflammatory and apoptotic signals. Aberrant methylation-induced silencing of ASC has been observed in a variety of cancer cells, thus implicating ASC in tumor suppression, althou...
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| Veröffentlicht in: | PloS one 2017-01, Vol.12 (1), p.e0169340-e0169340 |
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| creator | Kitazawa, Masato Hida, Shigeaki Fujii, Chifumi Taniguchi, Shun'ichiro Ito, Kensuke Matsumura, Tomio Okada, Nagisa Sakaizawa, Takashi Kobayashi, Akira Takeoka, Michiko Miyagawa, Shin-Ichi |
| description | ASC (apoptosis-associated speck-like protein containing a CARD) is a key adaptor molecule of inflammasomes that mediates inflammatory and apoptotic signals. Aberrant methylation-induced silencing of ASC has been observed in a variety of cancer cells, thus implicating ASC in tumor suppression, although this role remains incompletely defined especially in the context of closely neighboring cell proliferation. As ASC has been confirmed to be silenced by abnormal methylation in HT1080 fibrosarcoma cells as well, this cell line was investigated to characterize the precise role and mechanism of ASC in tumor progression. The effects of ASC were examined using in vitro cell cultures based on comparisons between low and high cell density conditions as well as in a xenograft murine model. ASC overexpression was established by insertion of the ASC gene into pcDNA3 and pMX-IRES-GFP vectors, the latter being packed into a retrovirus and subjected to reproducible competitive assays using parental cells as an internal control, for evaluation of cell viability. p21 and p53 were silenced using shRNA. Cell viability was suppressed in ASC-expressing transfectants as compared with control cells at high cell density conditions in in vitro culture and colony formation assays and in in vivo ectopic tumor formation trials. This suppression was not detected in low cell density conditions. Furthermore, remarkable progression of apoptosis was observed in ASC-introduced cells at a high cell density, but not at a low one. ASC-dependent apoptosis was mediated not by p21, p53, or caspase-1, but rather by cleavage of caspase-9 as well as by suppression of the NF-κB-related X-linked inhibitor-of-apoptosis protein. Caspase-9 cleavage was observed to be dependent on gap junction formation. The remarkable effect of ASC on the induction of apoptosis through caspase-9 and gap junctions revealed in this study may lead to promising new approaches in anticancer therapy. |
| doi_str_mv | 10.1371/journal.pone.0169340 |
| format | Article |
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Aberrant methylation-induced silencing of ASC has been observed in a variety of cancer cells, thus implicating ASC in tumor suppression, although this role remains incompletely defined especially in the context of closely neighboring cell proliferation. As ASC has been confirmed to be silenced by abnormal methylation in HT1080 fibrosarcoma cells as well, this cell line was investigated to characterize the precise role and mechanism of ASC in tumor progression. The effects of ASC were examined using in vitro cell cultures based on comparisons between low and high cell density conditions as well as in a xenograft murine model. ASC overexpression was established by insertion of the ASC gene into pcDNA3 and pMX-IRES-GFP vectors, the latter being packed into a retrovirus and subjected to reproducible competitive assays using parental cells as an internal control, for evaluation of cell viability. p21 and p53 were silenced using shRNA. Cell viability was suppressed in ASC-expressing transfectants as compared with control cells at high cell density conditions in in vitro culture and colony formation assays and in in vivo ectopic tumor formation trials. This suppression was not detected in low cell density conditions. Furthermore, remarkable progression of apoptosis was observed in ASC-introduced cells at a high cell density, but not at a low one. ASC-dependent apoptosis was mediated not by p21, p53, or caspase-1, but rather by cleavage of caspase-9 as well as by suppression of the NF-κB-related X-linked inhibitor-of-apoptosis protein. Caspase-9 cleavage was observed to be dependent on gap junction formation. The remarkable effect of ASC on the induction of apoptosis through caspase-9 and gap junctions revealed in this study may lead to promising new approaches in anticancer therapy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0169340</identifier><identifier>PMID: 28056049</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aberration ; Animal models ; Apoptosis ; Apoptosis - genetics ; Apoptosis - physiology ; Biology and Life Sciences ; Blotting, Western ; Breast cancer ; Cancer ; Cancer cells ; CARD Signaling Adaptor Proteins ; Caspase ; Caspase 9 - genetics ; Caspase 9 - metabolism ; Caspase-1 ; Caspase-9 ; Caspases ; Cell Communication - genetics ; Cell Communication - physiology ; Cell culture ; Cell cycle ; Cell density ; Cell Line, Tumor ; Cell proliferation ; Cell signaling ; Cell Survival ; Cleavage ; Cloning ; Colorectal cancer ; Communication ; Connexin 43 - genetics ; Cyclin-dependent kinase inhibitor p21 ; Cytoskeletal Proteins - genetics ; Cytoskeletal Proteins - metabolism ; Density ; Fibrosarcoma ; Gap junctions ; Gap Junctions - metabolism ; Humans ; Immunohistochemistry ; In Situ Nick-End Labeling ; Inflammasomes ; Inflammation ; Medicine ; Medicine and Health Sciences ; Melanoma ; Methylation ; NF-κB protein ; Oncology ; p53 Protein ; Proteins ; Research and analysis methods ; Retroviridae ; Reverse Transcriptase Polymerase Chain Reaction ; rho GTP-Binding Proteins - genetics ; RNA, Small Interfering - genetics ; Surgery ; Tumor suppression ; Tumor Suppressor Protein p53 - genetics ; Tumorigenesis ; University graduates ; Xenografts</subject><ispartof>PloS one, 2017-01, Vol.12 (1), p.e0169340-e0169340</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Kitazawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://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>2017 Kitazawa et al 2017 Kitazawa et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c791t-d7b3b8edff9a452089ba3863c767841b45a202d183cfd76c61d413be9e0338883</citedby><cites>FETCH-LOGICAL-c791t-d7b3b8edff9a452089ba3863c767841b45a202d183cfd76c61d413be9e0338883</cites><orcidid>0000-0001-7737-7592</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215782/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215782/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23864,27922,27923,53789,53791,79370,79371</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28056049$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ahmad, Aamir</contributor><creatorcontrib>Kitazawa, Masato</creatorcontrib><creatorcontrib>Hida, Shigeaki</creatorcontrib><creatorcontrib>Fujii, Chifumi</creatorcontrib><creatorcontrib>Taniguchi, Shun'ichiro</creatorcontrib><creatorcontrib>Ito, Kensuke</creatorcontrib><creatorcontrib>Matsumura, Tomio</creatorcontrib><creatorcontrib>Okada, Nagisa</creatorcontrib><creatorcontrib>Sakaizawa, Takashi</creatorcontrib><creatorcontrib>Kobayashi, Akira</creatorcontrib><creatorcontrib>Takeoka, Michiko</creatorcontrib><creatorcontrib>Miyagawa, Shin-Ichi</creatorcontrib><title>ASC Induces Apoptosis via Activation of Caspase-9 by Enhancing Gap Junction-Mediated Intercellular Communication</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>ASC (apoptosis-associated speck-like protein containing a CARD) is a key adaptor molecule of inflammasomes that mediates inflammatory and apoptotic signals. Aberrant methylation-induced silencing of ASC has been observed in a variety of cancer cells, thus implicating ASC in tumor suppression, although this role remains incompletely defined especially in the context of closely neighboring cell proliferation. As ASC has been confirmed to be silenced by abnormal methylation in HT1080 fibrosarcoma cells as well, this cell line was investigated to characterize the precise role and mechanism of ASC in tumor progression. The effects of ASC were examined using in vitro cell cultures based on comparisons between low and high cell density conditions as well as in a xenograft murine model. ASC overexpression was established by insertion of the ASC gene into pcDNA3 and pMX-IRES-GFP vectors, the latter being packed into a retrovirus and subjected to reproducible competitive assays using parental cells as an internal control, for evaluation of cell viability. p21 and p53 were silenced using shRNA. Cell viability was suppressed in ASC-expressing transfectants as compared with control cells at high cell density conditions in in vitro culture and colony formation assays and in in vivo ectopic tumor formation trials. This suppression was not detected in low cell density conditions. Furthermore, remarkable progression of apoptosis was observed in ASC-introduced cells at a high cell density, but not at a low one. ASC-dependent apoptosis was mediated not by p21, p53, or caspase-1, but rather by cleavage of caspase-9 as well as by suppression of the NF-κB-related X-linked inhibitor-of-apoptosis protein. Caspase-9 cleavage was observed to be dependent on gap junction formation. The remarkable effect of ASC on the induction of apoptosis through caspase-9 and gap junctions revealed in this study may lead to promising new approaches in anticancer therapy.</description><subject>Aberration</subject><subject>Animal models</subject><subject>Apoptosis</subject><subject>Apoptosis - genetics</subject><subject>Apoptosis - physiology</subject><subject>Biology and Life Sciences</subject><subject>Blotting, Western</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer cells</subject><subject>CARD Signaling Adaptor Proteins</subject><subject>Caspase</subject><subject>Caspase 9 - genetics</subject><subject>Caspase 9 - metabolism</subject><subject>Caspase-1</subject><subject>Caspase-9</subject><subject>Caspases</subject><subject>Cell Communication - genetics</subject><subject>Cell Communication - physiology</subject><subject>Cell culture</subject><subject>Cell cycle</subject><subject>Cell density</subject><subject>Cell Line, Tumor</subject><subject>Cell proliferation</subject><subject>Cell signaling</subject><subject>Cell Survival</subject><subject>Cleavage</subject><subject>Cloning</subject><subject>Colorectal cancer</subject><subject>Communication</subject><subject>Connexin 43 - genetics</subject><subject>Cyclin-dependent kinase inhibitor p21</subject><subject>Cytoskeletal Proteins - genetics</subject><subject>Cytoskeletal Proteins - metabolism</subject><subject>Density</subject><subject>Fibrosarcoma</subject><subject>Gap junctions</subject><subject>Gap Junctions - metabolism</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>In Situ Nick-End Labeling</subject><subject>Inflammasomes</subject><subject>Inflammation</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Melanoma</subject><subject>Methylation</subject><subject>NF-κB protein</subject><subject>Oncology</subject><subject>p53 Protein</subject><subject>Proteins</subject><subject>Research and analysis methods</subject><subject>Retroviridae</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>rho GTP-Binding Proteins - genetics</subject><subject>RNA, Small Interfering - genetics</subject><subject>Surgery</subject><subject>Tumor suppression</subject><subject>Tumor Suppressor Protein p53 - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agriculture Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>ProQuest Biological Science Journals</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kitazawa, Masato</au><au>Hida, Shigeaki</au><au>Fujii, Chifumi</au><au>Taniguchi, Shun'ichiro</au><au>Ito, Kensuke</au><au>Matsumura, Tomio</au><au>Okada, Nagisa</au><au>Sakaizawa, Takashi</au><au>Kobayashi, Akira</au><au>Takeoka, Michiko</au><au>Miyagawa, Shin-Ichi</au><au>Ahmad, Aamir</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ASC Induces Apoptosis via Activation of Caspase-9 by Enhancing Gap Junction-Mediated Intercellular Communication</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-01-05</date><risdate>2017</risdate><volume>12</volume><issue>1</issue><spage>e0169340</spage><epage>e0169340</epage><pages>e0169340-e0169340</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>ASC (apoptosis-associated speck-like protein containing a CARD) is a key adaptor molecule of inflammasomes that mediates inflammatory and apoptotic signals. Aberrant methylation-induced silencing of ASC has been observed in a variety of cancer cells, thus implicating ASC in tumor suppression, although this role remains incompletely defined especially in the context of closely neighboring cell proliferation. As ASC has been confirmed to be silenced by abnormal methylation in HT1080 fibrosarcoma cells as well, this cell line was investigated to characterize the precise role and mechanism of ASC in tumor progression. The effects of ASC were examined using in vitro cell cultures based on comparisons between low and high cell density conditions as well as in a xenograft murine model. ASC overexpression was established by insertion of the ASC gene into pcDNA3 and pMX-IRES-GFP vectors, the latter being packed into a retrovirus and subjected to reproducible competitive assays using parental cells as an internal control, for evaluation of cell viability. p21 and p53 were silenced using shRNA. Cell viability was suppressed in ASC-expressing transfectants as compared with control cells at high cell density conditions in in vitro culture and colony formation assays and in in vivo ectopic tumor formation trials. This suppression was not detected in low cell density conditions. Furthermore, remarkable progression of apoptosis was observed in ASC-introduced cells at a high cell density, but not at a low one. ASC-dependent apoptosis was mediated not by p21, p53, or caspase-1, but rather by cleavage of caspase-9 as well as by suppression of the NF-κB-related X-linked inhibitor-of-apoptosis protein. Caspase-9 cleavage was observed to be dependent on gap junction formation. The remarkable effect of ASC on the induction of apoptosis through caspase-9 and gap junctions revealed in this study may lead to promising new approaches in anticancer therapy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28056049</pmid><doi>10.1371/journal.pone.0169340</doi><tpages>e0169340</tpages><orcidid>https://orcid.org/0000-0001-7737-7592</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-01, Vol.12 (1), p.e0169340-e0169340 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1855775941 |
| source | PLoS (Open access); MEDLINE; Full-Text Journals in Chemistry (Open access); PubMed Central (PMC); DOAJ Directory of Open Access Journals; EZB Electronic Journals Library |
| subjects | Aberration Animal models Apoptosis Apoptosis - genetics Apoptosis - physiology Biology and Life Sciences Blotting, Western Breast cancer Cancer Cancer cells CARD Signaling Adaptor Proteins Caspase Caspase 9 - genetics Caspase 9 - metabolism Caspase-1 Caspase-9 Caspases Cell Communication - genetics Cell Communication - physiology Cell culture Cell cycle Cell density Cell Line, Tumor Cell proliferation Cell signaling Cell Survival Cleavage Cloning Colorectal cancer Communication Connexin 43 - genetics Cyclin-dependent kinase inhibitor p21 Cytoskeletal Proteins - genetics Cytoskeletal Proteins - metabolism Density Fibrosarcoma Gap junctions Gap Junctions - metabolism Humans Immunohistochemistry In Situ Nick-End Labeling Inflammasomes Inflammation Medicine Medicine and Health Sciences Melanoma Methylation NF-κB protein Oncology p53 Protein Proteins Research and analysis methods Retroviridae Reverse Transcriptase Polymerase Chain Reaction rho GTP-Binding Proteins - genetics RNA, Small Interfering - genetics Surgery Tumor suppression Tumor Suppressor Protein p53 - genetics Tumorigenesis University graduates Xenografts |
| title | ASC Induces Apoptosis via Activation of Caspase-9 by Enhancing Gap Junction-Mediated Intercellular Communication |
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