Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance
Abstract Objective Chemoresistance is a critical feature of advanced ovarian cancer with only 30% of patients surviving longer than 5 years. We have previously shown that four kallikrein‐related (KLK) peptidases, KLK4, KLK5, KLK6 and KLK7 (KLK4–7), are implicated in peritoneal invasion and tumour gr...
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Veröffentlicht in: | Gynecologic oncology 2012-12, Vol.127 (3), p.569-578 |
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description | Abstract Objective Chemoresistance is a critical feature of advanced ovarian cancer with only 30% of patients surviving longer than 5 years. We have previously shown that four kallikrein‐related (KLK) peptidases, KLK4, KLK5, KLK6 and KLK7 (KLK4–7), are implicated in peritoneal invasion and tumour growth, but underlying mechanisms were not identified. We also reported that KLK7 overexpression confers chemoresistance to paclitaxel, and cell survival via integrins. In this study, we further explored the functional consequenses of overexpression of all four KLKs (KLK4–7) simultaneously in the ovarian cancer cell line, OV‐MZ‐6, and its impact on integrin expression and signalling, cell adhesion and survival as contributors to chemoresistance and metastatic progression. Methods Quantitative gene and protein expression analyses, confocal microscopy, cell adhesion and chemosensitivity assays were performed. Results Expression of α5β1/αvβ3 integrins was downregulated upon combined stable KLK4–7 overexpression in OV‐MZ‐6 cells. Accordingly, the adhesion of these cells to vitronectin and fibronectin, the extracellular matrix binding proteins of α5β1/αvβ3 integrins and two predominant proteins of the peritoneal matrix, was decreased. KLK4–7‐transfected cells were more resistant to paclitaxel (10–100 nmol/L: 38–54%), but not to carboplatin, which was associated with decreased apoptotic stimuli. However, the KLK4–7‐induced paclitaxel resistance was not blocked by the MEK1/2 inhibitor, U0126. Conclusions This study demonstrates that combined KLK4–7 expression by ovarian cancer cells promotes reduced integrin expression with consequently less cell–matrix attachment, and insensitivity to paclitaxel mediated by complex integrin and MAPK independent interactions, indicative of a malignant phenotype and disease progression suggesting a role for these KLKs in this process. |
doi_str_mv | 10.1016/j.ygyno.2012.09.001 |
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We have previously shown that four kallikrein‐related (KLK) peptidases, KLK4, KLK5, KLK6 and KLK7 (KLK4–7), are implicated in peritoneal invasion and tumour growth, but underlying mechanisms were not identified. We also reported that KLK7 overexpression confers chemoresistance to paclitaxel, and cell survival via integrins. In this study, we further explored the functional consequenses of overexpression of all four KLKs (KLK4–7) simultaneously in the ovarian cancer cell line, OV‐MZ‐6, and its impact on integrin expression and signalling, cell adhesion and survival as contributors to chemoresistance and metastatic progression. Methods Quantitative gene and protein expression analyses, confocal microscopy, cell adhesion and chemosensitivity assays were performed. Results Expression of α5β1/αvβ3 integrins was downregulated upon combined stable KLK4–7 overexpression in OV‐MZ‐6 cells. Accordingly, the adhesion of these cells to vitronectin and fibronectin, the extracellular matrix binding proteins of α5β1/αvβ3 integrins and two predominant proteins of the peritoneal matrix, was decreased. KLK4–7‐transfected cells were more resistant to paclitaxel (10–100 nmol/L: 38–54%), but not to carboplatin, which was associated with decreased apoptotic stimuli. However, the KLK4–7‐induced paclitaxel resistance was not blocked by the MEK1/2 inhibitor, U0126. Conclusions This study demonstrates that combined KLK4–7 expression by ovarian cancer cells promotes reduced integrin expression with consequently less cell–matrix attachment, and insensitivity to paclitaxel mediated by complex integrin and MAPK independent interactions, indicative of a malignant phenotype and disease progression suggesting a role for these KLKs in this process.</description><identifier>ISSN: 0090-8258</identifier><identifier>EISSN: 1095-6859</identifier><identifier>DOI: 10.1016/j.ygyno.2012.09.001</identifier><identifier>PMID: 22964375</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adhesion ; Antineoplastic Agents, Phytogenic - pharmacology ; Antineoplastic Agents, Phytogenic - therapeutic use ; Cell Adhesion - drug effects ; Cell Line, Tumor ; Chemoresistance ; Drug Resistance, Neoplasm - drug effects ; Female ; Gene Expression Regulation, Neoplastic ; Hematology, Oncology and Palliative Medicine ; Humans ; Integrins ; Integrins - metabolism ; Kallikreins ; Kallikreins - genetics ; Kallikreins - physiology ; MAP Kinase Signaling System ; Obstetrics and Gynecology ; Ovarian cancer ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - metabolism ; Ovarian Neoplasms - pathology ; Paclitaxel - pharmacology ; Paclitaxel - therapeutic use</subject><ispartof>Gynecologic oncology, 2012-12, Vol.127 (3), p.569-578</ispartof><rights>Elsevier B.V.</rights><rights>2012 Elsevier B.V.</rights><rights>Copyright © 2012 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c414t-c30baf6490dbbbfed9a6df094a7d791f4825c2bae6dceea5498e18cb8fb484743</citedby><cites>FETCH-LOGICAL-c414t-c30baf6490dbbbfed9a6df094a7d791f4825c2bae6dceea5498e18cb8fb484743</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ygyno.2012.09.001$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22964375$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Loessner, Daniela</creatorcontrib><creatorcontrib>Quent, Verena M.C</creatorcontrib><creatorcontrib>Kraemer, Julia</creatorcontrib><creatorcontrib>Weber, Eva C</creatorcontrib><creatorcontrib>Hutmacher, Dietmar W</creatorcontrib><creatorcontrib>Magdolen, Viktor</creatorcontrib><creatorcontrib>Clements, Judith A</creatorcontrib><title>Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance</title><title>Gynecologic oncology</title><addtitle>Gynecol Oncol</addtitle><description>Abstract Objective Chemoresistance is a critical feature of advanced ovarian cancer with only 30% of patients surviving longer than 5 years. We have previously shown that four kallikrein‐related (KLK) peptidases, KLK4, KLK5, KLK6 and KLK7 (KLK4–7), are implicated in peritoneal invasion and tumour growth, but underlying mechanisms were not identified. We also reported that KLK7 overexpression confers chemoresistance to paclitaxel, and cell survival via integrins. In this study, we further explored the functional consequenses of overexpression of all four KLKs (KLK4–7) simultaneously in the ovarian cancer cell line, OV‐MZ‐6, and its impact on integrin expression and signalling, cell adhesion and survival as contributors to chemoresistance and metastatic progression. Methods Quantitative gene and protein expression analyses, confocal microscopy, cell adhesion and chemosensitivity assays were performed. Results Expression of α5β1/αvβ3 integrins was downregulated upon combined stable KLK4–7 overexpression in OV‐MZ‐6 cells. Accordingly, the adhesion of these cells to vitronectin and fibronectin, the extracellular matrix binding proteins of α5β1/αvβ3 integrins and two predominant proteins of the peritoneal matrix, was decreased. KLK4–7‐transfected cells were more resistant to paclitaxel (10–100 nmol/L: 38–54%), but not to carboplatin, which was associated with decreased apoptotic stimuli. However, the KLK4–7‐induced paclitaxel resistance was not blocked by the MEK1/2 inhibitor, U0126. Conclusions This study demonstrates that combined KLK4–7 expression by ovarian cancer cells promotes reduced integrin expression with consequently less cell–matrix attachment, and insensitivity to paclitaxel mediated by complex integrin and MAPK independent interactions, indicative of a malignant phenotype and disease progression suggesting a role for these KLKs in this process.</description><subject>Adhesion</subject><subject>Antineoplastic Agents, Phytogenic - pharmacology</subject><subject>Antineoplastic Agents, Phytogenic - therapeutic use</subject><subject>Cell Adhesion - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Chemoresistance</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Humans</subject><subject>Integrins</subject><subject>Integrins - metabolism</subject><subject>Kallikreins</subject><subject>Kallikreins - genetics</subject><subject>Kallikreins - physiology</subject><subject>MAP Kinase Signaling System</subject><subject>Obstetrics and Gynecology</subject><subject>Ovarian cancer</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Paclitaxel - pharmacology</subject><subject>Paclitaxel - therapeutic use</subject><issn>0090-8258</issn><issn>1095-6859</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUsuO1DAQtBCIHRa-AAn5yGET2onz8AEkNOKlHYkDcLb86LAeMvZgJ6vNP_DRODMLBy5c2pa6qlpd1YQ8Z1AyYO2rfbl8X3woK2BVCaIEYA_IhoFoirZvxEOyARBQ9FXTX5AnKe0BoM7Yx-SiqkTL667ZkF_bcNDOo6V4d4yYkguehoFe76751VqbU22vqPJ2_XVULzTcquiUp0Z5g5EaHMdER1Q20SlQiyaiSllT2Rs8Ka7kozKjm9QdjoXzdja5b27wEPJUl6ZV6Sl5NKgx4bP795J8e__u6_Zjsfv84dP27a4wnPGpMDVoNbRcgNVaD2iFau0AgqvOdoINPK9sKq2wtQZRNVz0yHqj-0Hznne8viQvz7rHGH7OmCZ5cGldQnkMc5KMNayDtupFhtZnqIkhpYiDPEZ3UHGRDOQag9zLUwxyjUGCkDmGzHpxP2DWB7R_OX98z4DXZwDmNW8dRpmMw2yBdRHNJG1w_xnw5h9-9tY7o8YfuGDahzn67KBkMmWO_LJewnoIrALoal7VvwEC_a_u</recordid><startdate>20121201</startdate><enddate>20121201</enddate><creator>Loessner, Daniela</creator><creator>Quent, Verena M.C</creator><creator>Kraemer, Julia</creator><creator>Weber, Eva C</creator><creator>Hutmacher, Dietmar W</creator><creator>Magdolen, Viktor</creator><creator>Clements, Judith A</creator><general>Elsevier Inc</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>7X8</scope></search><sort><creationdate>20121201</creationdate><title>Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance</title><author>Loessner, Daniela ; Quent, Verena M.C ; Kraemer, Julia ; Weber, Eva C ; Hutmacher, Dietmar W ; Magdolen, Viktor ; Clements, Judith A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c414t-c30baf6490dbbbfed9a6df094a7d791f4825c2bae6dceea5498e18cb8fb484743</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adhesion</topic><topic>Antineoplastic Agents, Phytogenic - pharmacology</topic><topic>Antineoplastic Agents, Phytogenic - therapeutic use</topic><topic>Cell Adhesion - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Chemoresistance</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Humans</topic><topic>Integrins</topic><topic>Integrins - metabolism</topic><topic>Kallikreins</topic><topic>Kallikreins - genetics</topic><topic>Kallikreins - physiology</topic><topic>MAP Kinase Signaling System</topic><topic>Obstetrics and Gynecology</topic><topic>Ovarian cancer</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - metabolism</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Paclitaxel - pharmacology</topic><topic>Paclitaxel - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Loessner, Daniela</creatorcontrib><creatorcontrib>Quent, Verena M.C</creatorcontrib><creatorcontrib>Kraemer, Julia</creatorcontrib><creatorcontrib>Weber, Eva C</creatorcontrib><creatorcontrib>Hutmacher, Dietmar W</creatorcontrib><creatorcontrib>Magdolen, Viktor</creatorcontrib><creatorcontrib>Clements, Judith A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Gynecologic oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Loessner, Daniela</au><au>Quent, Verena M.C</au><au>Kraemer, Julia</au><au>Weber, Eva C</au><au>Hutmacher, Dietmar W</au><au>Magdolen, Viktor</au><au>Clements, Judith A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance</atitle><jtitle>Gynecologic oncology</jtitle><addtitle>Gynecol Oncol</addtitle><date>2012-12-01</date><risdate>2012</risdate><volume>127</volume><issue>3</issue><spage>569</spage><epage>578</epage><pages>569-578</pages><issn>0090-8258</issn><eissn>1095-6859</eissn><abstract>Abstract Objective Chemoresistance is a critical feature of advanced ovarian cancer with only 30% of patients surviving longer than 5 years. We have previously shown that four kallikrein‐related (KLK) peptidases, KLK4, KLK5, KLK6 and KLK7 (KLK4–7), are implicated in peritoneal invasion and tumour growth, but underlying mechanisms were not identified. We also reported that KLK7 overexpression confers chemoresistance to paclitaxel, and cell survival via integrins. In this study, we further explored the functional consequenses of overexpression of all four KLKs (KLK4–7) simultaneously in the ovarian cancer cell line, OV‐MZ‐6, and its impact on integrin expression and signalling, cell adhesion and survival as contributors to chemoresistance and metastatic progression. Methods Quantitative gene and protein expression analyses, confocal microscopy, cell adhesion and chemosensitivity assays were performed. Results Expression of α5β1/αvβ3 integrins was downregulated upon combined stable KLK4–7 overexpression in OV‐MZ‐6 cells. Accordingly, the adhesion of these cells to vitronectin and fibronectin, the extracellular matrix binding proteins of α5β1/αvβ3 integrins and two predominant proteins of the peritoneal matrix, was decreased. KLK4–7‐transfected cells were more resistant to paclitaxel (10–100 nmol/L: 38–54%), but not to carboplatin, which was associated with decreased apoptotic stimuli. However, the KLK4–7‐induced paclitaxel resistance was not blocked by the MEK1/2 inhibitor, U0126. Conclusions This study demonstrates that combined KLK4–7 expression by ovarian cancer cells promotes reduced integrin expression with consequently less cell–matrix attachment, and insensitivity to paclitaxel mediated by complex integrin and MAPK independent interactions, indicative of a malignant phenotype and disease progression suggesting a role for these KLKs in this process.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>22964375</pmid><doi>10.1016/j.ygyno.2012.09.001</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adhesion Antineoplastic Agents, Phytogenic - pharmacology Antineoplastic Agents, Phytogenic - therapeutic use Cell Adhesion - drug effects Cell Line, Tumor Chemoresistance Drug Resistance, Neoplasm - drug effects Female Gene Expression Regulation, Neoplastic Hematology, Oncology and Palliative Medicine Humans Integrins Integrins - metabolism Kallikreins Kallikreins - genetics Kallikreins - physiology MAP Kinase Signaling System Obstetrics and Gynecology Ovarian cancer Ovarian Neoplasms - drug therapy Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Paclitaxel - pharmacology Paclitaxel - therapeutic use |
title | Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance |
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