Claudin-4 activity in ovarian tumor cell apoptosis resistance and migration
Claudin-4 is a transmembrane protein expressed at high levels in the majority of epithelial ovarian tumors, irrespective of subtype, and has been associated with tumor cells that are both chemoresistant and highly mobile. The objective of this study was to determine the functional role that claudin-...
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| Veröffentlicht in: | BMC cancer 2016-10, Vol.16 (1), p.788-788, Article 788 |
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| creator | Hicks, Douglas A Galimanis, Carly E Webb, Patricia G Spillman, Monique A Behbakht, Kian Neville, Margaret C Baumgartner, Heidi K |
| description | Claudin-4 is a transmembrane protein expressed at high levels in the majority of epithelial ovarian tumors, irrespective of subtype, and has been associated with tumor cells that are both chemoresistant and highly mobile. The objective of this study was to determine the functional role that claudin-4 plays in apoptosis resistance and migration as well as the therapeutic utility of targeting claudin-4 activity with a small mimic peptide.
We examined claudin-4 activity in human ovarian tumor cell lines (SKOV3, OVCAR3, PEO4) using in vitro caspase and scratch assays as well as an in vivo mouse model of ovarian cancer. Claudin-4 activity was disrupted by treating cells with a small peptide that mimics the DFYNP sequence in the second extracellular loop of claudin-4. Claudin-4 expression was also altered using shRNA-mediated gene silencing.
Both the disruption of claudin-4 activity and the loss of claudin-4 expression significantly increased tumor cell caspase-3 activation (4 to 10-fold, respectively) in response to the apoptotic inducer staurosporine and reduced tumor cell migration by 50 %. The mimic peptide had no effect on cells that lacked claudin-4 expression. Female athymic nude mice bearing ZsGreen-PEO4 ovarian tumors showed a significant decrease in ovarian tumor burden, due to increased apoptosis, after treatment with intraperitoneal injections of 4 mg/kg mimic peptide every 48 h for three weeks, compared to control peptide treated mice.
Claudin-4 functionally contributes to both ovarian tumor cell apoptosis resistance and migration and targeting extracellular loop interactions of claudin-4 may have therapeutic implications for reducing ovarian tumor burden. |
| doi_str_mv | 10.1186/s12885-016-2799-7 |
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We examined claudin-4 activity in human ovarian tumor cell lines (SKOV3, OVCAR3, PEO4) using in vitro caspase and scratch assays as well as an in vivo mouse model of ovarian cancer. Claudin-4 activity was disrupted by treating cells with a small peptide that mimics the DFYNP sequence in the second extracellular loop of claudin-4. Claudin-4 expression was also altered using shRNA-mediated gene silencing.
Both the disruption of claudin-4 activity and the loss of claudin-4 expression significantly increased tumor cell caspase-3 activation (4 to 10-fold, respectively) in response to the apoptotic inducer staurosporine and reduced tumor cell migration by 50 %. The mimic peptide had no effect on cells that lacked claudin-4 expression. Female athymic nude mice bearing ZsGreen-PEO4 ovarian tumors showed a significant decrease in ovarian tumor burden, due to increased apoptosis, after treatment with intraperitoneal injections of 4 mg/kg mimic peptide every 48 h for three weeks, compared to control peptide treated mice.
Claudin-4 functionally contributes to both ovarian tumor cell apoptosis resistance and migration and targeting extracellular loop interactions of claudin-4 may have therapeutic implications for reducing ovarian tumor burden.</description><identifier>ISSN: 1471-2407</identifier><identifier>EISSN: 1471-2407</identifier><identifier>DOI: 10.1186/s12885-016-2799-7</identifier><identifier>PMID: 27724921</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>Animals ; Apoptosis ; Apoptosis - genetics ; Caspase 3 - metabolism ; Cell culture ; Cell Line, Tumor ; Cell Movement - genetics ; Cell Survival - genetics ; Claudin-4 - genetics ; Claudin-4 - metabolism ; Development and progression ; Disease Models, Animal ; Female ; Gene Expression Regulation, Neoplastic ; Genetic aspects ; Heterografts ; Humans ; Immunohistochemistry ; Laboratories ; Membrane proteins ; Mice ; Miracles ; Motility ; Ovarian cancer ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - metabolism ; Ovarian Neoplasms - pathology ; Peptides ; Physiological aspects ; Proteins ; RNA Interference ; RNA, Small Interfering - genetics ; Tumor Burden ; Tumors</subject><ispartof>BMC cancer, 2016-10, Vol.16 (1), p.788-788, Article 788</ispartof><rights>COPYRIGHT 2016 BioMed Central Ltd.</rights><rights>Copyright BioMed Central 2016</rights><rights>The Author(s). 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c586t-80f3122e28458cb1b3067f29460015c95787d385f594ac699846c4443e42d2ca3</citedby><cites>FETCH-LOGICAL-c586t-80f3122e28458cb1b3067f29460015c95787d385f594ac699846c4443e42d2ca3</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/PMC5057472/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5057472/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27724921$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hicks, Douglas A</creatorcontrib><creatorcontrib>Galimanis, Carly E</creatorcontrib><creatorcontrib>Webb, Patricia G</creatorcontrib><creatorcontrib>Spillman, Monique A</creatorcontrib><creatorcontrib>Behbakht, Kian</creatorcontrib><creatorcontrib>Neville, Margaret C</creatorcontrib><creatorcontrib>Baumgartner, Heidi K</creatorcontrib><title>Claudin-4 activity in ovarian tumor cell apoptosis resistance and migration</title><title>BMC cancer</title><addtitle>BMC Cancer</addtitle><description>Claudin-4 is a transmembrane protein expressed at high levels in the majority of epithelial ovarian tumors, irrespective of subtype, and has been associated with tumor cells that are both chemoresistant and highly mobile. The objective of this study was to determine the functional role that claudin-4 plays in apoptosis resistance and migration as well as the therapeutic utility of targeting claudin-4 activity with a small mimic peptide.
We examined claudin-4 activity in human ovarian tumor cell lines (SKOV3, OVCAR3, PEO4) using in vitro caspase and scratch assays as well as an in vivo mouse model of ovarian cancer. Claudin-4 activity was disrupted by treating cells with a small peptide that mimics the DFYNP sequence in the second extracellular loop of claudin-4. Claudin-4 expression was also altered using shRNA-mediated gene silencing.
Both the disruption of claudin-4 activity and the loss of claudin-4 expression significantly increased tumor cell caspase-3 activation (4 to 10-fold, respectively) in response to the apoptotic inducer staurosporine and reduced tumor cell migration by 50 %. The mimic peptide had no effect on cells that lacked claudin-4 expression. Female athymic nude mice bearing ZsGreen-PEO4 ovarian tumors showed a significant decrease in ovarian tumor burden, due to increased apoptosis, after treatment with intraperitoneal injections of 4 mg/kg mimic peptide every 48 h for three weeks, compared to control peptide treated mice.
Claudin-4 functionally contributes to both ovarian tumor cell apoptosis resistance and migration and targeting extracellular loop interactions of claudin-4 may have therapeutic implications for reducing ovarian tumor burden.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - genetics</subject><subject>Caspase 3 - metabolism</subject><subject>Cell culture</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - genetics</subject><subject>Cell Survival - genetics</subject><subject>Claudin-4 - genetics</subject><subject>Claudin-4 - metabolism</subject><subject>Development and progression</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genetic aspects</subject><subject>Heterografts</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Laboratories</subject><subject>Membrane proteins</subject><subject>Mice</subject><subject>Miracles</subject><subject>Motility</subject><subject>Ovarian cancer</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Peptides</subject><subject>Physiological aspects</subject><subject>Proteins</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering - genetics</subject><subject>Tumor Burden</subject><subject>Tumors</subject><issn>1471-2407</issn><issn>1471-2407</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNpdkkuLHCEUhSUkZB7JD8hmEAJhsqjEZ6mbQNPkMWQgkMdabMvqdqjSHrWazL-PNT2ZdGejgt8913s8ALzC6B3Gsn2fMZGSNwi3DRFKNeIJOMVM4IYwJJ4enE_AWc43CGEhkXwOTogQhCmCT8HX5WCmzoeGQWOL3_lyB32AcWeSNwGWaYwJWjcM0GzjtsTsM0yursUE66AJHRz9OpniY3gBnvVmyO7lw34Ofn36-HP5pbn-9vlqubhuLJdtaSTqKSbEEcm4tCu8oqgVPVGsrQ_kVnEhRUcl77lixrZKSdZaxhh1jHTEGnoOPux1t9NqdJ11oSQz6G3yo0l3Ohqvj2-C3-h13GmOuGCCVIHLB4EUbyeXix59noc0wcUpaywpp62UiFb09X_oTZxSqOPdU_UDqsf_qLUZnPahj7WvnUX1ggnEpVL3Wm-PKBtDcb_L2kw566sf34_ZNwfsxpmhbHIcptnnfAziPWhTzDm5_tEHjPScEr1Pia4p0XNKtKg1F4cGPlb8jQX9A5uCtGE</recordid><startdate>20161011</startdate><enddate>20161011</enddate><creator>Hicks, Douglas A</creator><creator>Galimanis, Carly E</creator><creator>Webb, Patricia G</creator><creator>Spillman, Monique A</creator><creator>Behbakht, Kian</creator><creator>Neville, Margaret C</creator><creator>Baumgartner, Heidi K</creator><general>BioMed Central Ltd</general><general>BioMed Central</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>ISR</scope><scope>3V.</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20161011</creationdate><title>Claudin-4 activity in ovarian tumor cell apoptosis resistance and migration</title><author>Hicks, Douglas A ; 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The objective of this study was to determine the functional role that claudin-4 plays in apoptosis resistance and migration as well as the therapeutic utility of targeting claudin-4 activity with a small mimic peptide.
We examined claudin-4 activity in human ovarian tumor cell lines (SKOV3, OVCAR3, PEO4) using in vitro caspase and scratch assays as well as an in vivo mouse model of ovarian cancer. Claudin-4 activity was disrupted by treating cells with a small peptide that mimics the DFYNP sequence in the second extracellular loop of claudin-4. Claudin-4 expression was also altered using shRNA-mediated gene silencing.
Both the disruption of claudin-4 activity and the loss of claudin-4 expression significantly increased tumor cell caspase-3 activation (4 to 10-fold, respectively) in response to the apoptotic inducer staurosporine and reduced tumor cell migration by 50 %. The mimic peptide had no effect on cells that lacked claudin-4 expression. Female athymic nude mice bearing ZsGreen-PEO4 ovarian tumors showed a significant decrease in ovarian tumor burden, due to increased apoptosis, after treatment with intraperitoneal injections of 4 mg/kg mimic peptide every 48 h for three weeks, compared to control peptide treated mice.
Claudin-4 functionally contributes to both ovarian tumor cell apoptosis resistance and migration and targeting extracellular loop interactions of claudin-4 may have therapeutic implications for reducing ovarian tumor burden.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>27724921</pmid><doi>10.1186/s12885-016-2799-7</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis Apoptosis - genetics Caspase 3 - metabolism Cell culture Cell Line, Tumor Cell Movement - genetics Cell Survival - genetics Claudin-4 - genetics Claudin-4 - metabolism Development and progression Disease Models, Animal Female Gene Expression Regulation, Neoplastic Genetic aspects Heterografts Humans Immunohistochemistry Laboratories Membrane proteins Mice Miracles Motility Ovarian cancer Ovarian Neoplasms - genetics Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Peptides Physiological aspects Proteins RNA Interference RNA, Small Interfering - genetics Tumor Burden Tumors |
| title | Claudin-4 activity in ovarian tumor cell apoptosis resistance and migration |
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