Epigenetic silencing of argininosuccinate synthetase confers resistance to platinum‐induced cell death but collateral sensitivity to arginine auxotrophy in ovarian cancer
Evidence indicates that acquired resistance of cancers to chemotherapeutic agents can occur via epigenetic mechanisms. Down‐regulation of expression of argininosuccinate synthetase (ASS1), the rate‐limiting enzyme in the biosynthesis of arginine, has been associated with the development of platinum...
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| creator | Nicholson, Linda J. Smith, Paul R. Hiller, Louise Szlosarek, Peter W. Kimberley, Christopher Sehouli, Jalid Koensgen, Dominique Mustea, Alexander Schmid, Peter Crook, Tim |
| description | Evidence indicates that acquired resistance of cancers to chemotherapeutic agents can occur via epigenetic mechanisms. Down‐regulation of expression of argininosuccinate synthetase (ASS1), the rate‐limiting enzyme in the biosynthesis of arginine, has been associated with the development of platinum resistance in ovarian cancer treated with platinum‐based chemotherapy. The aim of the present study was to analyse epigenetic regulation of ASS1 in ovarian cancer tissue taken at diagnosis and relapse and determine its significance as a predictor of clinical outcome in patients treated with platinum‐based chemotherapy. In addition, expression and epigenetic regulation of ASS1 were analysed in human ovarian cancer cell lines, and ASS1 expression correlated with the ability of the lines to grow in media containing cisplatin, carboplatin or taxol or in arginine‐depleted media. Our results show that aberrant methylation in the ASS1 promoter correlated with transcriptional silencing in ovarian cancer cell lines. ASS1 silencing conferred selective resistance to platinum‐based drugs and conferred arginine auxotrophy and sensitivity to arginine deprivation. In ovarian cancer, ASS1 methylation at diagnosis was associated with significantly reduced overall survival (p = 0.01) and relapse‐free survival (p = 0.01). In patients who relapse, ASS1 methylation was significantly more frequent at relapse (p = 0.008). These data establish epigenetic inactivation of ASS1 as a determinant of response to platinum chemotherapy and imply that transcriptional silencing of ASS1 contributes to treatment failure and clinical relapse in ovarian cancer. The collateral sensitivity of cells lacking endogenous ASS1 to arginine depletion suggests novel therapeutic strategies for the management of relapsed ovarian cancer. © 2009 UICC |
| doi_str_mv | 10.1002/ijc.24546 |
| format | Article |
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Down‐regulation of expression of argininosuccinate synthetase (ASS1), the rate‐limiting enzyme in the biosynthesis of arginine, has been associated with the development of platinum resistance in ovarian cancer treated with platinum‐based chemotherapy. The aim of the present study was to analyse epigenetic regulation of ASS1 in ovarian cancer tissue taken at diagnosis and relapse and determine its significance as a predictor of clinical outcome in patients treated with platinum‐based chemotherapy. In addition, expression and epigenetic regulation of ASS1 were analysed in human ovarian cancer cell lines, and ASS1 expression correlated with the ability of the lines to grow in media containing cisplatin, carboplatin or taxol or in arginine‐depleted media. Our results show that aberrant methylation in the ASS1 promoter correlated with transcriptional silencing in ovarian cancer cell lines. ASS1 silencing conferred selective resistance to platinum‐based drugs and conferred arginine auxotrophy and sensitivity to arginine deprivation. In ovarian cancer, ASS1 methylation at diagnosis was associated with significantly reduced overall survival (p = 0.01) and relapse‐free survival (p = 0.01). In patients who relapse, ASS1 methylation was significantly more frequent at relapse (p = 0.008). These data establish epigenetic inactivation of ASS1 as a determinant of response to platinum chemotherapy and imply that transcriptional silencing of ASS1 contributes to treatment failure and clinical relapse in ovarian cancer. The collateral sensitivity of cells lacking endogenous ASS1 to arginine depletion suggests novel therapeutic strategies for the management of relapsed ovarian cancer. © 2009 UICC</description><identifier>ISSN: 0020-7136</identifier><identifier>EISSN: 1097-0215</identifier><identifier>DOI: 10.1002/ijc.24546</identifier><identifier>PMID: 19533750</identifier><identifier>CODEN: IJCNAW</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Arginine - deficiency ; Argininosuccinate Synthase - antagonists & inhibitors ; Argininosuccinate Synthase - genetics ; Argininosuccinate Synthase - metabolism ; argininosuccinate synthetase (ASS1) ; Biological and medical sciences ; Carboplatin - administration & dosage ; Cell Death ; chemotherapy ; Cisplatin - administration & dosage ; Cystadenocarcinoma, Serous - drug therapy ; Cystadenocarcinoma, Serous - genetics ; Cystadenocarcinoma, Serous - pathology ; DNA Methylation ; Drug Resistance, Neoplasm ; Female ; Female genital diseases ; Gene Expression Regulation, Neoplastic - drug effects ; Gene Silencing ; Gynecology. Andrology. Obstetrics ; Humans ; Immunoblotting ; Medical sciences ; methylation ; Middle Aged ; ovarian cancer ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - pathology ; Paclitaxel - administration & dosage ; Promoter Regions, Genetic - genetics ; Survival Rate ; Tumor Cells, Cultured ; Tumors</subject><ispartof>International journal of cancer, 2009-09, Vol.125 (6), p.1454-1463</ispartof><rights>Copyright © 2009 UICC</rights><rights>2009 INIST-CNRS</rights><rights>2009 UICC</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4866-3bc0a04a83253c167d55b72ade445d1def4eafedd05d40f53cb3e483480147703</citedby><cites>FETCH-LOGICAL-c4866-3bc0a04a83253c167d55b72ade445d1def4eafedd05d40f53cb3e483480147703</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fijc.24546$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fijc.24546$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21810099$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19533750$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nicholson, Linda J.</creatorcontrib><creatorcontrib>Smith, Paul R.</creatorcontrib><creatorcontrib>Hiller, Louise</creatorcontrib><creatorcontrib>Szlosarek, Peter W.</creatorcontrib><creatorcontrib>Kimberley, Christopher</creatorcontrib><creatorcontrib>Sehouli, Jalid</creatorcontrib><creatorcontrib>Koensgen, Dominique</creatorcontrib><creatorcontrib>Mustea, Alexander</creatorcontrib><creatorcontrib>Schmid, Peter</creatorcontrib><creatorcontrib>Crook, Tim</creatorcontrib><title>Epigenetic silencing of argininosuccinate synthetase confers resistance to platinum‐induced cell death but collateral sensitivity to arginine auxotrophy in ovarian cancer</title><title>International journal of cancer</title><addtitle>Int J Cancer</addtitle><description>Evidence indicates that acquired resistance of cancers to chemotherapeutic agents can occur via epigenetic mechanisms. Down‐regulation of expression of argininosuccinate synthetase (ASS1), the rate‐limiting enzyme in the biosynthesis of arginine, has been associated with the development of platinum resistance in ovarian cancer treated with platinum‐based chemotherapy. The aim of the present study was to analyse epigenetic regulation of ASS1 in ovarian cancer tissue taken at diagnosis and relapse and determine its significance as a predictor of clinical outcome in patients treated with platinum‐based chemotherapy. In addition, expression and epigenetic regulation of ASS1 were analysed in human ovarian cancer cell lines, and ASS1 expression correlated with the ability of the lines to grow in media containing cisplatin, carboplatin or taxol or in arginine‐depleted media. Our results show that aberrant methylation in the ASS1 promoter correlated with transcriptional silencing in ovarian cancer cell lines. ASS1 silencing conferred selective resistance to platinum‐based drugs and conferred arginine auxotrophy and sensitivity to arginine deprivation. In ovarian cancer, ASS1 methylation at diagnosis was associated with significantly reduced overall survival (p = 0.01) and relapse‐free survival (p = 0.01). In patients who relapse, ASS1 methylation was significantly more frequent at relapse (p = 0.008). These data establish epigenetic inactivation of ASS1 as a determinant of response to platinum chemotherapy and imply that transcriptional silencing of ASS1 contributes to treatment failure and clinical relapse in ovarian cancer. The collateral sensitivity of cells lacking endogenous ASS1 to arginine depletion suggests novel therapeutic strategies for the management of relapsed ovarian cancer. © 2009 UICC</description><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Arginine - deficiency</subject><subject>Argininosuccinate Synthase - antagonists & inhibitors</subject><subject>Argininosuccinate Synthase - genetics</subject><subject>Argininosuccinate Synthase - metabolism</subject><subject>argininosuccinate synthetase (ASS1)</subject><subject>Biological and medical sciences</subject><subject>Carboplatin - administration & dosage</subject><subject>Cell Death</subject><subject>chemotherapy</subject><subject>Cisplatin - administration & dosage</subject><subject>Cystadenocarcinoma, Serous - drug therapy</subject><subject>Cystadenocarcinoma, Serous - genetics</subject><subject>Cystadenocarcinoma, Serous - pathology</subject><subject>DNA Methylation</subject><subject>Drug Resistance, Neoplasm</subject><subject>Female</subject><subject>Female genital diseases</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gene Silencing</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Medical sciences</subject><subject>methylation</subject><subject>Middle Aged</subject><subject>ovarian cancer</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Paclitaxel - administration & dosage</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Survival Rate</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><issn>0020-7136</issn><issn>1097-0215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUFu1DAUhi0EokNhwQWQN4BYpLVjO8ks0ahAUSU2sI5e7JcZVxk72E4hO47AQTgVJ8FhIljBypL9vf-T30_IU84uOGPlpb3VF6VUsrpHNpxt64KVXN0nm_zGipqL6ow8ivGWMc4Vkw_JGd8qIWrFNuTH1Wj36DBZTaMd0Gnr9tT3FMLeOut8nHS-goQ0zi4dMEFEqr3rMUQaMNqYwGmkydNxgGTddPz57bt1ZtJoqMZhoAYhHWg3pTw3ZAYDDDSiizbZO5vmZXbVIYXpq0_Bj4eZWkf9HQQLjurFER6TBz0MEZ-s5zn59Obq4-5dcfPh7fXu9U2hZVNVheg0AyahEaUSmle1UaqrSzAopTLcYC8RejSGKSNZn5lOoGyEbBiXdc3EOXl5yh2D_zxhTO3RxuUr4NBPsa1lxZqqaXgmX_yXrPKSG662GXx1AnXwMQbs2zHYI4S55axdSmxzie3vEjP7bA2duiOav-TaWgaerwBEDUMf8nZs_MOVvMmJ20V6eeK-5Gbnfxvb6_e7k_oX43O5MQ</recordid><startdate>20090915</startdate><enddate>20090915</enddate><creator>Nicholson, Linda J.</creator><creator>Smith, Paul R.</creator><creator>Hiller, Louise</creator><creator>Szlosarek, Peter W.</creator><creator>Kimberley, Christopher</creator><creator>Sehouli, Jalid</creator><creator>Koensgen, Dominique</creator><creator>Mustea, Alexander</creator><creator>Schmid, Peter</creator><creator>Crook, Tim</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley-Blackwell</general><scope>IQODW</scope><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><scope>7TM</scope></search><sort><creationdate>20090915</creationdate><title>Epigenetic silencing of argininosuccinate synthetase confers resistance to platinum‐induced cell death but collateral sensitivity to arginine auxotrophy in ovarian cancer</title><author>Nicholson, Linda J. ; Smith, Paul R. ; Hiller, Louise ; Szlosarek, Peter W. ; Kimberley, Christopher ; Sehouli, Jalid ; Koensgen, Dominique ; Mustea, Alexander ; Schmid, Peter ; Crook, Tim</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4866-3bc0a04a83253c167d55b72ade445d1def4eafedd05d40f53cb3e483480147703</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Arginine - deficiency</topic><topic>Argininosuccinate Synthase - antagonists & inhibitors</topic><topic>Argininosuccinate Synthase - genetics</topic><topic>Argininosuccinate Synthase - metabolism</topic><topic>argininosuccinate synthetase (ASS1)</topic><topic>Biological and medical sciences</topic><topic>Carboplatin - administration & dosage</topic><topic>Cell Death</topic><topic>chemotherapy</topic><topic>Cisplatin - administration & dosage</topic><topic>Cystadenocarcinoma, Serous - drug therapy</topic><topic>Cystadenocarcinoma, Serous - genetics</topic><topic>Cystadenocarcinoma, Serous - pathology</topic><topic>DNA Methylation</topic><topic>Drug Resistance, Neoplasm</topic><topic>Female</topic><topic>Female genital diseases</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Gene Silencing</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Medical sciences</topic><topic>methylation</topic><topic>Middle Aged</topic><topic>ovarian cancer</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - genetics</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Paclitaxel - administration & dosage</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Survival Rate</topic><topic>Tumor Cells, Cultured</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nicholson, Linda J.</creatorcontrib><creatorcontrib>Smith, Paul R.</creatorcontrib><creatorcontrib>Hiller, Louise</creatorcontrib><creatorcontrib>Szlosarek, Peter W.</creatorcontrib><creatorcontrib>Kimberley, Christopher</creatorcontrib><creatorcontrib>Sehouli, Jalid</creatorcontrib><creatorcontrib>Koensgen, Dominique</creatorcontrib><creatorcontrib>Mustea, Alexander</creatorcontrib><creatorcontrib>Schmid, Peter</creatorcontrib><creatorcontrib>Crook, Tim</creatorcontrib><collection>Pascal-Francis</collection><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><collection>Nucleic Acids Abstracts</collection><jtitle>International journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nicholson, Linda J.</au><au>Smith, Paul R.</au><au>Hiller, Louise</au><au>Szlosarek, Peter W.</au><au>Kimberley, Christopher</au><au>Sehouli, Jalid</au><au>Koensgen, Dominique</au><au>Mustea, Alexander</au><au>Schmid, Peter</au><au>Crook, Tim</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Epigenetic silencing of argininosuccinate synthetase confers resistance to platinum‐induced cell death but collateral sensitivity to arginine auxotrophy in ovarian cancer</atitle><jtitle>International journal of cancer</jtitle><addtitle>Int J Cancer</addtitle><date>2009-09-15</date><risdate>2009</risdate><volume>125</volume><issue>6</issue><spage>1454</spage><epage>1463</epage><pages>1454-1463</pages><issn>0020-7136</issn><eissn>1097-0215</eissn><coden>IJCNAW</coden><abstract>Evidence indicates that acquired resistance of cancers to chemotherapeutic agents can occur via epigenetic mechanisms. Down‐regulation of expression of argininosuccinate synthetase (ASS1), the rate‐limiting enzyme in the biosynthesis of arginine, has been associated with the development of platinum resistance in ovarian cancer treated with platinum‐based chemotherapy. The aim of the present study was to analyse epigenetic regulation of ASS1 in ovarian cancer tissue taken at diagnosis and relapse and determine its significance as a predictor of clinical outcome in patients treated with platinum‐based chemotherapy. In addition, expression and epigenetic regulation of ASS1 were analysed in human ovarian cancer cell lines, and ASS1 expression correlated with the ability of the lines to grow in media containing cisplatin, carboplatin or taxol or in arginine‐depleted media. Our results show that aberrant methylation in the ASS1 promoter correlated with transcriptional silencing in ovarian cancer cell lines. ASS1 silencing conferred selective resistance to platinum‐based drugs and conferred arginine auxotrophy and sensitivity to arginine deprivation. In ovarian cancer, ASS1 methylation at diagnosis was associated with significantly reduced overall survival (p = 0.01) and relapse‐free survival (p = 0.01). In patients who relapse, ASS1 methylation was significantly more frequent at relapse (p = 0.008). These data establish epigenetic inactivation of ASS1 as a determinant of response to platinum chemotherapy and imply that transcriptional silencing of ASS1 contributes to treatment failure and clinical relapse in ovarian cancer. The collateral sensitivity of cells lacking endogenous ASS1 to arginine depletion suggests novel therapeutic strategies for the management of relapsed ovarian cancer. © 2009 UICC</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>19533750</pmid><doi>10.1002/ijc.24546</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | International journal of cancer, 2009-09, Vol.125 (6), p.1454-1463 |
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| subjects | Antineoplastic Combined Chemotherapy Protocols - therapeutic use Arginine - deficiency Argininosuccinate Synthase - antagonists & inhibitors Argininosuccinate Synthase - genetics Argininosuccinate Synthase - metabolism argininosuccinate synthetase (ASS1) Biological and medical sciences Carboplatin - administration & dosage Cell Death chemotherapy Cisplatin - administration & dosage Cystadenocarcinoma, Serous - drug therapy Cystadenocarcinoma, Serous - genetics Cystadenocarcinoma, Serous - pathology DNA Methylation Drug Resistance, Neoplasm Female Female genital diseases Gene Expression Regulation, Neoplastic - drug effects Gene Silencing Gynecology. Andrology. Obstetrics Humans Immunoblotting Medical sciences methylation Middle Aged ovarian cancer Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Ovarian Neoplasms - pathology Paclitaxel - administration & dosage Promoter Regions, Genetic - genetics Survival Rate Tumor Cells, Cultured Tumors |
| title | Epigenetic silencing of argininosuccinate synthetase confers resistance to platinum‐induced cell death but collateral sensitivity to arginine auxotrophy in ovarian cancer |
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