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The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX
Background/Aims The FRA16D fragile site gene WWOX is a tumor suppressor that participates in p53-mediated apoptosis. The c-jun N-terminal kinase JNK1 interacts with WWOX and inhibits apoptosis. We investigated the function of WWOX in human hepatocellular carcinoma (HCC) and the effect of JNK inhibit...
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| Published in: | Journal of hepatology 2008-09, Vol.49 (3), p.373-383 |
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| creator | Aderca, Ileana Moser, Catherine D Veerasamy, Manivannan Bani-Hani, Ahmad H Bonilla-Guerrero, Ruben Ahmed, Kadra Shire, Abdirashid Cazanave, Sophie C Montoya, Damian P Mettler, Teresa A Burgart, Lawrence J Nagorney, David M Thibodeau, Stephen N Cunningham, Julie M Lai, Jin-Ping Roberts, Lewis R |
| description | Background/Aims The FRA16D fragile site gene WWOX is a tumor suppressor that participates in p53-mediated apoptosis. The c-jun N-terminal kinase JNK1 interacts with WWOX and inhibits apoptosis. We investigated the function of WWOX in human hepatocellular carcinoma (HCC) and the effect of JNK inhibition on WWOX-mediated apoptosis. Methods Allelic imbalance on chromosome 16 was analyzed in 73 HCCs using 53 microsatellite markers. WWOX mRNA in HCC cell lines and primary HCCs was measured by real-time RT-PCR. Effects of WWOX on proliferation and apoptosis and the interaction between WWOX and JNK inhibition were examined. Results Loss on chromosome 16 occurred in 34 of 73 HCCs. Of 11 HCC cell lines, 2 had low, 7 intermediate, and 2 had high WWOX mRNA. Of 51 primary tumors, 23 had low WWOX mRNA. Forced expression of WWOX in SNU387 cells decreased FGF2-mediated proliferation and enhanced apoptosis induced by staurosporine and the JNK inhibitor SP600129. Conversely, knockdown of WWOX in SNU449 cells using shRNA targeting WWOX increased proliferation and resistance to SP600129-induced apoptosis. Conclusions WWOX induces apoptosis and inhibits human HCC cell growth through a mechanism enhanced by JNK inhibition. |
| doi_str_mv | 10.1016/j.jhep.2008.05.015 |
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The c-jun N-terminal kinase JNK1 interacts with WWOX and inhibits apoptosis. We investigated the function of WWOX in human hepatocellular carcinoma (HCC) and the effect of JNK inhibition on WWOX-mediated apoptosis. Methods Allelic imbalance on chromosome 16 was analyzed in 73 HCCs using 53 microsatellite markers. WWOX mRNA in HCC cell lines and primary HCCs was measured by real-time RT-PCR. Effects of WWOX on proliferation and apoptosis and the interaction between WWOX and JNK inhibition were examined. Results Loss on chromosome 16 occurred in 34 of 73 HCCs. Of 11 HCC cell lines, 2 had low, 7 intermediate, and 2 had high WWOX mRNA. Of 51 primary tumors, 23 had low WWOX mRNA. Forced expression of WWOX in SNU387 cells decreased FGF2-mediated proliferation and enhanced apoptosis induced by staurosporine and the JNK inhibitor SP600129. Conversely, knockdown of WWOX in SNU449 cells using shRNA targeting WWOX increased proliferation and resistance to SP600129-induced apoptosis. Conclusions WWOX induces apoptosis and inhibits human HCC cell growth through a mechanism enhanced by JNK inhibition.</description><identifier>ISSN: 0168-8278</identifier><identifier>EISSN: 1600-0641</identifier><identifier>DOI: 10.1016/j.jhep.2008.05.015</identifier><identifier>PMID: 18620777</identifier><identifier>CODEN: JOHEEC</identifier><language>eng</language><publisher>Oxford: Elsevier B.V</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Apoptosis ; Apoptosis - drug effects ; Biological and medical sciences ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Hepatocellular - pathology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Chromosomes, Human, Pair 16 - genetics ; Enzyme Inhibitors - pharmacology ; Female ; Gastroenterology and Hepatology ; Gastroenterology. Liver. Pancreas. Abdomen ; Gene Expression Regulation ; Hepatocellular carcinoma ; Humans ; JNK ; Liver Neoplasms - metabolism ; Liver Neoplasms - pathology ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Loss of Heterozygosity - genetics ; Male ; Medical sciences ; Middle Aged ; Mitogen-Activated Protein Kinase 8 - antagonists & inhibitors ; Mitogen-Activated Protein Kinase 8 - metabolism ; Oxidoreductases - genetics ; Oxidoreductases - metabolism ; RNA, Messenger - metabolism ; Staurosporine - pharmacology ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism ; Tumors ; WW Domain-Containing Oxidoreductase ; WWOX</subject><ispartof>Journal of hepatology, 2008-09, Vol.49 (3), p.373-383</ispartof><rights>European Association for the Study of the Liver</rights><rights>2008 European Association for the Study of the Liver</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c538t-c06e2218c0a101eca1c70dad9b702edb7472c55651b97411316942afef31cf303</citedby><cites>FETCH-LOGICAL-c538t-c06e2218c0a101eca1c70dad9b702edb7472c55651b97411316942afef31cf303</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,27957,27958</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20627781$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18620777$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Aderca, Ileana</creatorcontrib><creatorcontrib>Moser, Catherine D</creatorcontrib><creatorcontrib>Veerasamy, Manivannan</creatorcontrib><creatorcontrib>Bani-Hani, Ahmad H</creatorcontrib><creatorcontrib>Bonilla-Guerrero, Ruben</creatorcontrib><creatorcontrib>Ahmed, Kadra</creatorcontrib><creatorcontrib>Shire, Abdirashid</creatorcontrib><creatorcontrib>Cazanave, Sophie C</creatorcontrib><creatorcontrib>Montoya, Damian P</creatorcontrib><creatorcontrib>Mettler, Teresa A</creatorcontrib><creatorcontrib>Burgart, Lawrence J</creatorcontrib><creatorcontrib>Nagorney, David M</creatorcontrib><creatorcontrib>Thibodeau, Stephen N</creatorcontrib><creatorcontrib>Cunningham, Julie M</creatorcontrib><creatorcontrib>Lai, Jin-Ping</creatorcontrib><creatorcontrib>Roberts, Lewis R</creatorcontrib><title>The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX</title><title>Journal of hepatology</title><addtitle>J Hepatol</addtitle><description>Background/Aims The FRA16D fragile site gene WWOX is a tumor suppressor that participates in p53-mediated apoptosis. The c-jun N-terminal kinase JNK1 interacts with WWOX and inhibits apoptosis. We investigated the function of WWOX in human hepatocellular carcinoma (HCC) and the effect of JNK inhibition on WWOX-mediated apoptosis. Methods Allelic imbalance on chromosome 16 was analyzed in 73 HCCs using 53 microsatellite markers. WWOX mRNA in HCC cell lines and primary HCCs was measured by real-time RT-PCR. Effects of WWOX on proliferation and apoptosis and the interaction between WWOX and JNK inhibition were examined. Results Loss on chromosome 16 occurred in 34 of 73 HCCs. Of 11 HCC cell lines, 2 had low, 7 intermediate, and 2 had high WWOX mRNA. Of 51 primary tumors, 23 had low WWOX mRNA. Forced expression of WWOX in SNU387 cells decreased FGF2-mediated proliferation and enhanced apoptosis induced by staurosporine and the JNK inhibitor SP600129. Conversely, knockdown of WWOX in SNU449 cells using shRNA targeting WWOX increased proliferation and resistance to SP600129-induced apoptosis. Conclusions WWOX induces apoptosis and inhibits human HCC cell growth through a mechanism enhanced by JNK inhibition.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Biological and medical sciences</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Chromosomes, Human, Pair 16 - genetics</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Female</subject><subject>Gastroenterology and Hepatology</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Gene Expression Regulation</subject><subject>Hepatocellular carcinoma</subject><subject>Humans</subject><subject>JNK</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - pathology</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Loss of Heterozygosity - genetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Mitogen-Activated Protein Kinase 8 - antagonists & inhibitors</subject><subject>Mitogen-Activated Protein Kinase 8 - metabolism</subject><subject>Oxidoreductases - genetics</subject><subject>Oxidoreductases - metabolism</subject><subject>RNA, Messenger - metabolism</subject><subject>Staurosporine - pharmacology</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumor Suppressor Proteins - metabolism</subject><subject>Tumors</subject><subject>WW Domain-Containing Oxidoreductase</subject><subject>WWOX</subject><issn>0168-8278</issn><issn>1600-0641</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><recordid>eNp9kk1v1DAQhiMEokvhD3BAvsAtYex8OJFQpWoFFKgoUovKzXKcCXHIxsFOKu2_Z6JdlY8DJ1vy874znnei6DmHhAMvXvdJ3-GUCIAygTwBnj-INrwAiKHI-MNoQ1AZl0KWJ9GTEHoASKHKHkcnvCwESCk3kbrpkH38_InZsbO1nZ1n11_IgouK4djp0WBgenLT7IINzLXsYrtlBochkKRZDDas3rOZXOZlR-qwTJPHEOh6e3v17Wn0qNVDwGfH8zT6-u7tzfYivrx6_2F7fhmbPC3n2ECBQvDSgKavodHcSGh0U9USBDa1zKQweV7kvK5kxnnKiyoTusU25aZNIT2Nzg6-01LvsDE4zl4PavJ2p_1eOW3V3y-j7dR3d6dELrOqKsng1dHAu58LhlntbFj_qUd0S1BUjwsaKIHiABrvQvDY3hfhoNZcVK_WXNSai4JcUS4kevFne78lxyAIeHkEdDB6aD1N3oZ7TkAhpCw5cW8OHNIw7yx6FYxFSqmxHs2sGmf_38fZP3Iz2NFSxR-4x9C7xY8Uk-IqCAXqet2gdYGgpN2hVtNfrMe_5g</recordid><startdate>20080901</startdate><enddate>20080901</enddate><creator>Aderca, Ileana</creator><creator>Moser, Catherine D</creator><creator>Veerasamy, Manivannan</creator><creator>Bani-Hani, Ahmad H</creator><creator>Bonilla-Guerrero, Ruben</creator><creator>Ahmed, Kadra</creator><creator>Shire, Abdirashid</creator><creator>Cazanave, Sophie C</creator><creator>Montoya, Damian P</creator><creator>Mettler, Teresa A</creator><creator>Burgart, Lawrence J</creator><creator>Nagorney, David M</creator><creator>Thibodeau, Stephen N</creator><creator>Cunningham, Julie M</creator><creator>Lai, Jin-Ping</creator><creator>Roberts, Lewis R</creator><general>Elsevier B.V</general><general>Elsevier</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>5PM</scope></search><sort><creationdate>20080901</creationdate><title>The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX</title><author>Aderca, Ileana ; Moser, Catherine D ; Veerasamy, Manivannan ; Bani-Hani, Ahmad H ; Bonilla-Guerrero, Ruben ; Ahmed, Kadra ; Shire, Abdirashid ; Cazanave, Sophie C ; Montoya, Damian P ; Mettler, Teresa A ; Burgart, Lawrence J ; Nagorney, David M ; Thibodeau, Stephen N ; Cunningham, Julie M ; Lai, Jin-Ping ; Roberts, Lewis R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c538t-c06e2218c0a101eca1c70dad9b702edb7472c55651b97411316942afef31cf303</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Biological and medical sciences</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Chromosomes, Human, Pair 16 - genetics</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Female</topic><topic>Gastroenterology and Hepatology</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Gene Expression Regulation</topic><topic>Hepatocellular carcinoma</topic><topic>Humans</topic><topic>JNK</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - pathology</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Loss of Heterozygosity - genetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Mitogen-Activated Protein Kinase 8 - antagonists & inhibitors</topic><topic>Mitogen-Activated Protein Kinase 8 - metabolism</topic><topic>Oxidoreductases - genetics</topic><topic>Oxidoreductases - metabolism</topic><topic>RNA, Messenger - metabolism</topic><topic>Staurosporine - pharmacology</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - metabolism</topic><topic>Tumors</topic><topic>WW Domain-Containing Oxidoreductase</topic><topic>WWOX</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Aderca, Ileana</creatorcontrib><creatorcontrib>Moser, Catherine D</creatorcontrib><creatorcontrib>Veerasamy, Manivannan</creatorcontrib><creatorcontrib>Bani-Hani, Ahmad H</creatorcontrib><creatorcontrib>Bonilla-Guerrero, Ruben</creatorcontrib><creatorcontrib>Ahmed, Kadra</creatorcontrib><creatorcontrib>Shire, Abdirashid</creatorcontrib><creatorcontrib>Cazanave, Sophie C</creatorcontrib><creatorcontrib>Montoya, Damian P</creatorcontrib><creatorcontrib>Mettler, Teresa A</creatorcontrib><creatorcontrib>Burgart, Lawrence J</creatorcontrib><creatorcontrib>Nagorney, David M</creatorcontrib><creatorcontrib>Thibodeau, Stephen N</creatorcontrib><creatorcontrib>Cunningham, Julie M</creatorcontrib><creatorcontrib>Lai, Jin-Ping</creatorcontrib><creatorcontrib>Roberts, Lewis R</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>PubMed Central (Full Participant titles)</collection><jtitle>Journal of hepatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Aderca, Ileana</au><au>Moser, Catherine D</au><au>Veerasamy, Manivannan</au><au>Bani-Hani, Ahmad H</au><au>Bonilla-Guerrero, Ruben</au><au>Ahmed, Kadra</au><au>Shire, Abdirashid</au><au>Cazanave, Sophie C</au><au>Montoya, Damian P</au><au>Mettler, Teresa A</au><au>Burgart, Lawrence J</au><au>Nagorney, David M</au><au>Thibodeau, Stephen N</au><au>Cunningham, Julie M</au><au>Lai, Jin-Ping</au><au>Roberts, Lewis R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX</atitle><jtitle>Journal of hepatology</jtitle><addtitle>J Hepatol</addtitle><date>2008-09-01</date><risdate>2008</risdate><volume>49</volume><issue>3</issue><spage>373</spage><epage>383</epage><pages>373-383</pages><issn>0168-8278</issn><eissn>1600-0641</eissn><coden>JOHEEC</coden><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Background/Aims The FRA16D fragile site gene WWOX is a tumor suppressor that participates in p53-mediated apoptosis. The c-jun N-terminal kinase JNK1 interacts with WWOX and inhibits apoptosis. We investigated the function of WWOX in human hepatocellular carcinoma (HCC) and the effect of JNK inhibition on WWOX-mediated apoptosis. Methods Allelic imbalance on chromosome 16 was analyzed in 73 HCCs using 53 microsatellite markers. WWOX mRNA in HCC cell lines and primary HCCs was measured by real-time RT-PCR. Effects of WWOX on proliferation and apoptosis and the interaction between WWOX and JNK inhibition were examined. Results Loss on chromosome 16 occurred in 34 of 73 HCCs. Of 11 HCC cell lines, 2 had low, 7 intermediate, and 2 had high WWOX mRNA. Of 51 primary tumors, 23 had low WWOX mRNA. Forced expression of WWOX in SNU387 cells decreased FGF2-mediated proliferation and enhanced apoptosis induced by staurosporine and the JNK inhibitor SP600129. Conversely, knockdown of WWOX in SNU449 cells using shRNA targeting WWOX increased proliferation and resistance to SP600129-induced apoptosis. Conclusions WWOX induces apoptosis and inhibits human HCC cell growth through a mechanism enhanced by JNK inhibition.</abstract><cop>Oxford</cop><pub>Elsevier B.V</pub><pmid>18620777</pmid><doi>10.1016/j.jhep.2008.05.015</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Aged Aged, 80 and over Apoptosis Apoptosis - drug effects Biological and medical sciences Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - pathology Cell Line, Tumor Cell Proliferation - drug effects Chromosomes, Human, Pair 16 - genetics Enzyme Inhibitors - pharmacology Female Gastroenterology and Hepatology Gastroenterology. Liver. Pancreas. Abdomen Gene Expression Regulation Hepatocellular carcinoma Humans JNK Liver Neoplasms - metabolism Liver Neoplasms - pathology Liver. Biliary tract. Portal circulation. Exocrine pancreas Loss of Heterozygosity - genetics Male Medical sciences Middle Aged Mitogen-Activated Protein Kinase 8 - antagonists & inhibitors Mitogen-Activated Protein Kinase 8 - metabolism Oxidoreductases - genetics Oxidoreductases - metabolism RNA, Messenger - metabolism Staurosporine - pharmacology Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Tumors WW Domain-Containing Oxidoreductase WWOX |
| title | The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX |
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