Activation of nuclear PTEN by inhibition of Notch signaling induces G2/M cell cycle arrest in gastric cancer
Mutation in PTEN has not yet been detected, but its function as a tumor suppressor is inactivated in many cancers. In this study we determined that, activated Notch signaling disables PTEN by phosphorylation and thereby contributes to gastric tumorigenesis. Notch inhibition by small interfering RNA...
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| Veröffentlicht in: | Oncogene 2016-01, Vol.35 (2), p.251-260 |
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| creator | Kim, S-J Lee, H-W Baek, J-H Cho, Y-H Kang, H G Jeong, J S Song, J Park, H-S Chun, K-H |
| description | Mutation in PTEN has not yet been detected, but its function as a tumor suppressor is inactivated in many cancers. In this study we determined that, activated Notch signaling disables PTEN by phosphorylation and thereby contributes to gastric tumorigenesis. Notch inhibition by small interfering RNA or γ-secretase inhibitor (GSI) induced mitotic arrest and apoptosis in gastric cancer cells. Notch inhibition induced dephosphorylation in the C-terminal domain of PTEN, which led to PTEN nuclear localization. Overexpression of activated Notch1-induced phosphorylation of PTEN and reversed GSI-induced mitotic arrest. Dephosphorylated nuclear PTEN caused prometaphase arrest by interaction with the cyclin B1-CDK1 complex, resulting in their accumulation in the nucleus and subsequent apoptosis. We found a correlation between high expression levels of Notch1 and low survival rates and, similarly, between reduced nuclear PTEN expression and increasing the TNM classification of malignant tumours stages in malignant tissues from gastric cancer patients. The growth of Notch1-depleted gastric tumors was significantly retarded in xenografted mice, and in addition, PTEN deletion restored growth similar to control tumors. We also demonstrated that combination treatment with GSI and chemotherapeutic agents significantly reduced the orthotopically transplanted gastric tumors in mice without noticeable toxicity. Overall, our findings suggest that inhibition of Notch signaling can be employed as a PTEN activator, making it a potential target for gastric cancer therapy. |
| doi_str_mv | 10.1038/onc.2015.80 |
| format | Article |
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In this study we determined that, activated Notch signaling disables PTEN by phosphorylation and thereby contributes to gastric tumorigenesis. Notch inhibition by small interfering RNA or γ-secretase inhibitor (GSI) induced mitotic arrest and apoptosis in gastric cancer cells. Notch inhibition induced dephosphorylation in the C-terminal domain of PTEN, which led to PTEN nuclear localization. Overexpression of activated Notch1-induced phosphorylation of PTEN and reversed GSI-induced mitotic arrest. Dephosphorylated nuclear PTEN caused prometaphase arrest by interaction with the cyclin B1-CDK1 complex, resulting in their accumulation in the nucleus and subsequent apoptosis. We found a correlation between high expression levels of Notch1 and low survival rates and, similarly, between reduced nuclear PTEN expression and increasing the TNM classification of malignant tumours stages in malignant tissues from gastric cancer patients. The growth of Notch1-depleted gastric tumors was significantly retarded in xenografted mice, and in addition, PTEN deletion restored growth similar to control tumors. We also demonstrated that combination treatment with GSI and chemotherapeutic agents significantly reduced the orthotopically transplanted gastric tumors in mice without noticeable toxicity. Overall, our findings suggest that inhibition of Notch signaling can be employed as a PTEN activator, making it a potential target for gastric cancer therapy.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2015.80</identifier><identifier>PMID: 25823029</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/105 ; 13/109 ; 13/2 ; 13/31 ; 13/89 ; 13/95 ; 14 ; 631/67/1504/1829 ; 64/60 ; Animals ; Apoptosis ; Apoptosis - drug effects ; Apoptosis - genetics ; Cancer therapies ; Cell Biology ; Cell cycle ; Cell Line, Tumor ; Cell Nucleus - metabolism ; Cellular signal transduction ; Chemotherapy ; Cyclin B1 ; Cyclin B1 - metabolism ; Dephosphorylation ; Development and progression ; Female ; G2 Phase Cell Cycle Checkpoints - drug effects ; Gastric cancer ; Gene Expression Regulation, Neoplastic ; Gene mutations ; Genetic aspects ; Health aspects ; Human Genetics ; Humans ; Internal Medicine ; Kinases ; Localization ; Medicine ; Medicine & Public Health ; Mice, Inbred BALB C ; Mutation ; Notch1 protein ; Oligopeptides - pharmacology ; Oncology ; original-article ; Phosphorylation ; PTEN Phosphohydrolase - genetics ; PTEN Phosphohydrolase - metabolism ; PTEN protein ; Receptor, Notch1 - genetics ; Receptor, Notch1 - metabolism ; Receptors, Notch - genetics ; Receptors, Notch - metabolism ; Secretase ; Signal Transduction ; siRNA ; Stomach cancer ; Stomach Neoplasms - drug therapy ; Stomach Neoplasms - metabolism ; Stomach Neoplasms - mortality ; Stomach Neoplasms - pathology ; Toxicity ; Tumor suppressor genes ; Tumorigenesis ; Tumors ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>Oncogene, 2016-01, Vol.35 (2), p.251-260</ispartof><rights>Macmillan Publishers Limited 2016</rights><rights>COPYRIGHT 2016 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jan 14, 2016</rights><rights>Macmillan Publishers Limited 2016.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c618t-dbbe305cac075fb638c6ce63f8e617e22a506c241c98b7f45bdb705b22c37363</citedby><cites>FETCH-LOGICAL-c618t-dbbe305cac075fb638c6ce63f8e617e22a506c241c98b7f45bdb705b22c37363</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/onc.2015.80$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2015.80$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25823029$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, S-J</creatorcontrib><creatorcontrib>Lee, H-W</creatorcontrib><creatorcontrib>Baek, J-H</creatorcontrib><creatorcontrib>Cho, Y-H</creatorcontrib><creatorcontrib>Kang, H G</creatorcontrib><creatorcontrib>Jeong, J S</creatorcontrib><creatorcontrib>Song, J</creatorcontrib><creatorcontrib>Park, H-S</creatorcontrib><creatorcontrib>Chun, K-H</creatorcontrib><title>Activation of nuclear PTEN by inhibition of Notch signaling induces G2/M cell cycle arrest in gastric cancer</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Mutation in PTEN has not yet been detected, but its function as a tumor suppressor is inactivated in many cancers. In this study we determined that, activated Notch signaling disables PTEN by phosphorylation and thereby contributes to gastric tumorigenesis. Notch inhibition by small interfering RNA or γ-secretase inhibitor (GSI) induced mitotic arrest and apoptosis in gastric cancer cells. Notch inhibition induced dephosphorylation in the C-terminal domain of PTEN, which led to PTEN nuclear localization. Overexpression of activated Notch1-induced phosphorylation of PTEN and reversed GSI-induced mitotic arrest. Dephosphorylated nuclear PTEN caused prometaphase arrest by interaction with the cyclin B1-CDK1 complex, resulting in their accumulation in the nucleus and subsequent apoptosis. We found a correlation between high expression levels of Notch1 and low survival rates and, similarly, between reduced nuclear PTEN expression and increasing the TNM classification of malignant tumours stages in malignant tissues from gastric cancer patients. The growth of Notch1-depleted gastric tumors was significantly retarded in xenografted mice, and in addition, PTEN deletion restored growth similar to control tumors. We also demonstrated that combination treatment with GSI and chemotherapeutic agents significantly reduced the orthotopically transplanted gastric tumors in mice without noticeable toxicity. Overall, our findings suggest that inhibition of Notch signaling can be employed as a PTEN activator, making it a potential target for gastric cancer therapy.</description><subject>13/1</subject><subject>13/105</subject><subject>13/109</subject><subject>13/2</subject><subject>13/31</subject><subject>13/89</subject><subject>13/95</subject><subject>14</subject><subject>631/67/1504/1829</subject><subject>64/60</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>Cancer therapies</subject><subject>Cell Biology</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cell Nucleus - metabolism</subject><subject>Cellular signal transduction</subject><subject>Chemotherapy</subject><subject>Cyclin B1</subject><subject>Cyclin B1 - metabolism</subject><subject>Dephosphorylation</subject><subject>Development and progression</subject><subject>Female</subject><subject>G2 Phase Cell Cycle Checkpoints - drug effects</subject><subject>Gastric cancer</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene mutations</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Kinases</subject><subject>Localization</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice, Inbred BALB C</subject><subject>Mutation</subject><subject>Notch1 protein</subject><subject>Oligopeptides - pharmacology</subject><subject>Oncology</subject><subject>original-article</subject><subject>Phosphorylation</subject><subject>PTEN Phosphohydrolase - genetics</subject><subject>PTEN Phosphohydrolase - metabolism</subject><subject>PTEN protein</subject><subject>Receptor, Notch1 - genetics</subject><subject>Receptor, Notch1 - metabolism</subject><subject>Receptors, Notch - genetics</subject><subject>Receptors, Notch - metabolism</subject><subject>Secretase</subject><subject>Signal Transduction</subject><subject>siRNA</subject><subject>Stomach cancer</subject><subject>Stomach Neoplasms - drug therapy</subject><subject>Stomach Neoplasms - metabolism</subject><subject>Stomach Neoplasms - mortality</subject><subject>Stomach Neoplasms - pathology</subject><subject>Toxicity</subject><subject>Tumor suppressor genes</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kttrFDEUxoModq0--S4BXwSdbS6TyzwupVahVh_2PSRnMtOU2aQmM8L-92bZ1htF8hDI9_vO-Q45CL2mZE0J12cpwpoRKtaaPEEr2irZCNG1T9GKdII0HePsBL0o5ZYQojrCnqMTJjTjhHUrNG1gDj_sHFLEacBxgcnbjL9tL66x2-MQb4ILD-p1muEGlzBGO4U4VrVfwBd8yc6-YPDThGFf_djm7MtcZTzaMucAGGwEn1-iZ4Odin91f5-i7ceL7fmn5urr5efzzVUDkuq56Z3znAiwQJQYnOQaJHjJB-0lVZ4xK4gE1lLotFNDK1zvFBGOMeCKS36K3h3L3uX0falJzC6UQzwbfVqKoUqKTmlFWEXf_oPepiXX8YphsqVCKNb9l6JKSEG5pu1varSTNyEOac4WDq3Npm1JRzUXqlLrR6h6er8LkKIfQn3_y_D-aICcSsl-MHc57GzeG0rMYQFMXQBzWACjSaXf3Edd3M73v9iHH6_AhyNQqhRHn_-Y5ZF6PwHSALbF</recordid><startdate>20160114</startdate><enddate>20160114</enddate><creator>Kim, S-J</creator><creator>Lee, H-W</creator><creator>Baek, J-H</creator><creator>Cho, Y-H</creator><creator>Kang, H G</creator><creator>Jeong, J S</creator><creator>Song, J</creator><creator>Park, H-S</creator><creator>Chun, K-H</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope></search><sort><creationdate>20160114</creationdate><title>Activation of nuclear PTEN by inhibition of Notch signaling induces G2/M cell cycle arrest in gastric cancer</title><author>Kim, S-J ; Lee, H-W ; Baek, J-H ; Cho, Y-H ; Kang, H G ; Jeong, J S ; Song, J ; Park, H-S ; Chun, K-H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c618t-dbbe305cac075fb638c6ce63f8e617e22a506c241c98b7f45bdb705b22c37363</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>13/1</topic><topic>13/105</topic><topic>13/109</topic><topic>13/2</topic><topic>13/31</topic><topic>13/89</topic><topic>13/95</topic><topic>14</topic><topic>631/67/1504/1829</topic><topic>64/60</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - 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genetics</topic><topic>PTEN Phosphohydrolase - metabolism</topic><topic>PTEN protein</topic><topic>Receptor, Notch1 - genetics</topic><topic>Receptor, Notch1 - metabolism</topic><topic>Receptors, Notch - genetics</topic><topic>Receptors, Notch - metabolism</topic><topic>Secretase</topic><topic>Signal Transduction</topic><topic>siRNA</topic><topic>Stomach cancer</topic><topic>Stomach Neoplasms - drug therapy</topic><topic>Stomach Neoplasms - metabolism</topic><topic>Stomach Neoplasms - mortality</topic><topic>Stomach Neoplasms - pathology</topic><topic>Toxicity</topic><topic>Tumor suppressor genes</topic><topic>Tumorigenesis</topic><topic>Tumors</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, S-J</creatorcontrib><creatorcontrib>Lee, H-W</creatorcontrib><creatorcontrib>Baek, J-H</creatorcontrib><creatorcontrib>Cho, Y-H</creatorcontrib><creatorcontrib>Kang, H G</creatorcontrib><creatorcontrib>Jeong, J S</creatorcontrib><creatorcontrib>Song, J</creatorcontrib><creatorcontrib>Park, H-S</creatorcontrib><creatorcontrib>Chun, K-H</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</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>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, S-J</au><au>Lee, H-W</au><au>Baek, J-H</au><au>Cho, Y-H</au><au>Kang, H G</au><au>Jeong, J S</au><au>Song, J</au><au>Park, H-S</au><au>Chun, K-H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activation of nuclear PTEN by inhibition of Notch signaling induces G2/M cell cycle arrest in gastric cancer</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2016-01-14</date><risdate>2016</risdate><volume>35</volume><issue>2</issue><spage>251</spage><epage>260</epage><pages>251-260</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>Mutation in PTEN has not yet been detected, but its function as a tumor suppressor is inactivated in many cancers. In this study we determined that, activated Notch signaling disables PTEN by phosphorylation and thereby contributes to gastric tumorigenesis. Notch inhibition by small interfering RNA or γ-secretase inhibitor (GSI) induced mitotic arrest and apoptosis in gastric cancer cells. Notch inhibition induced dephosphorylation in the C-terminal domain of PTEN, which led to PTEN nuclear localization. Overexpression of activated Notch1-induced phosphorylation of PTEN and reversed GSI-induced mitotic arrest. Dephosphorylated nuclear PTEN caused prometaphase arrest by interaction with the cyclin B1-CDK1 complex, resulting in their accumulation in the nucleus and subsequent apoptosis. We found a correlation between high expression levels of Notch1 and low survival rates and, similarly, between reduced nuclear PTEN expression and increasing the TNM classification of malignant tumours stages in malignant tissues from gastric cancer patients. The growth of Notch1-depleted gastric tumors was significantly retarded in xenografted mice, and in addition, PTEN deletion restored growth similar to control tumors. We also demonstrated that combination treatment with GSI and chemotherapeutic agents significantly reduced the orthotopically transplanted gastric tumors in mice without noticeable toxicity. Overall, our findings suggest that inhibition of Notch signaling can be employed as a PTEN activator, making it a potential target for gastric cancer therapy.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25823029</pmid><doi>10.1038/onc.2015.80</doi><tpages>10</tpages></addata></record> |
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| subjects | 13/1 13/105 13/109 13/2 13/31 13/89 13/95 14 631/67/1504/1829 64/60 Animals Apoptosis Apoptosis - drug effects Apoptosis - genetics Cancer therapies Cell Biology Cell cycle Cell Line, Tumor Cell Nucleus - metabolism Cellular signal transduction Chemotherapy Cyclin B1 Cyclin B1 - metabolism Dephosphorylation Development and progression Female G2 Phase Cell Cycle Checkpoints - drug effects Gastric cancer Gene Expression Regulation, Neoplastic Gene mutations Genetic aspects Health aspects Human Genetics Humans Internal Medicine Kinases Localization Medicine Medicine & Public Health Mice, Inbred BALB C Mutation Notch1 protein Oligopeptides - pharmacology Oncology original-article Phosphorylation PTEN Phosphohydrolase - genetics PTEN Phosphohydrolase - metabolism PTEN protein Receptor, Notch1 - genetics Receptor, Notch1 - metabolism Receptors, Notch - genetics Receptors, Notch - metabolism Secretase Signal Transduction siRNA Stomach cancer Stomach Neoplasms - drug therapy Stomach Neoplasms - metabolism Stomach Neoplasms - mortality Stomach Neoplasms - pathology Toxicity Tumor suppressor genes Tumorigenesis Tumors Xenograft Model Antitumor Assays Xenografts |
| title | Activation of nuclear PTEN by inhibition of Notch signaling induces G2/M cell cycle arrest in gastric cancer |
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