Caveolin-1 promotes tumor progression in an autochthonous mouse model of prostate cancer: genetic ablation of Cav-1 delays advanced prostate tumor development in tramp mice
Caveolin-1 (Cav-1) is the primary structural component of caveolae and is implicated in the processes of vesicular transport, cholesterol balance, transformation, and tumorigenesis. Despite an abundance of data suggesting that Cav-1 has transformation suppressor properties both in vitro and in vivo,...
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| Veröffentlicht in: | The Journal of biological chemistry 2005-07, Vol.280 (26), p.25134-25145 |
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| container_title | The Journal of biological chemistry |
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| creator | Williams, Terence M Hassan, Ghada S Li, Jiangwei Cohen, Alex W Medina, Freddy Frank, Philippe G Pestell, Richard G Di Vizio, Dolores Loda, Massimo Lisanti, Michael P |
| description | Caveolin-1 (Cav-1) is the primary structural component of caveolae and is implicated in the processes of vesicular transport, cholesterol balance, transformation, and tumorigenesis. Despite an abundance of data suggesting that Cav-1 has transformation suppressor properties both in vitro and in vivo, Cav-1 is expressed at increased levels in human prostate cancer. To investigate the role of Cav-1 in prostate cancer onset and progression, we interbred Cav-1(-/-) null mice with a TRAMP (transgenic adenocarcinoma of mouse prostate) model that spontaneously develops advanced prostate cancer and metastatic disease. We found that, although the loss of Cav-1 did not affect the appearance of minimally invasive prostate cancer, its absence significantly impeded progression to highly invasive and metastatic disease. Inactivation of one (+/-) or both (-/-) alleles of Cav-1 resulted in significant reductions in prostate tumor burden, as well as decreases in regional lymph node metastases. Moreover, further examination revealed decreased metastasis to distant organs, such as the lungs, in TRAMP/Cav-1(-/-) mice. Utilizing prostate carcinoma cell lines (C1, C2, and C3) derived from TRAMP tumors, we also showed a positive correlation between Cav-1 expression and the ability of these cells to form tumors in vivo. Furthermore, down-regulation of Cav-1 expression in these cells, using a small interfering RNA approach, significantly reduced their tumorigenic and metastatic potential. Mechanistically, we showed that loss or down-regulation of Cav-1 expression results in increased apoptosis, with increased prostate apoptosis response factor-4 and PTEN levels in Cav-1(-/-) null prostate tumors. Our current findings provide the first in vivo molecular genetic evidence that Cav-1 does indeed function as a tumor promoter during prostate carcinogenesis, rather than as a tumor suppressor. |
| doi_str_mv | 10.1074/jbc.M501186200 |
| format | Article |
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Despite an abundance of data suggesting that Cav-1 has transformation suppressor properties both in vitro and in vivo, Cav-1 is expressed at increased levels in human prostate cancer. To investigate the role of Cav-1 in prostate cancer onset and progression, we interbred Cav-1(-/-) null mice with a TRAMP (transgenic adenocarcinoma of mouse prostate) model that spontaneously develops advanced prostate cancer and metastatic disease. We found that, although the loss of Cav-1 did not affect the appearance of minimally invasive prostate cancer, its absence significantly impeded progression to highly invasive and metastatic disease. Inactivation of one (+/-) or both (-/-) alleles of Cav-1 resulted in significant reductions in prostate tumor burden, as well as decreases in regional lymph node metastases. Moreover, further examination revealed decreased metastasis to distant organs, such as the lungs, in TRAMP/Cav-1(-/-) mice. Utilizing prostate carcinoma cell lines (C1, C2, and C3) derived from TRAMP tumors, we also showed a positive correlation between Cav-1 expression and the ability of these cells to form tumors in vivo. Furthermore, down-regulation of Cav-1 expression in these cells, using a small interfering RNA approach, significantly reduced their tumorigenic and metastatic potential. Mechanistically, we showed that loss or down-regulation of Cav-1 expression results in increased apoptosis, with increased prostate apoptosis response factor-4 and PTEN levels in Cav-1(-/-) null prostate tumors. Our current findings provide the first in vivo molecular genetic evidence that Cav-1 does indeed function as a tumor promoter during prostate carcinogenesis, rather than as a tumor suppressor.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M501186200</identifier><identifier>PMID: 15802273</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Antigens, Polyomavirus Transforming - chemistry ; Apoptosis ; Caveolin 1 ; Caveolins - metabolism ; Caveolins - physiology ; Cell Line ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; Disease Models, Animal ; Disease Progression ; Down-Regulation ; Gene Expression Regulation, Neoplastic ; Genetic Vectors ; Immunohistochemistry ; In Situ Nick-End Labeling ; Lymphatic Metastasis ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neoplasm Metastasis ; Neoplasms - pathology ; Proliferating Cell Nuclear Antigen - metabolism ; Prostatic Neoplasms - metabolism ; RNA, Small Interfering - metabolism ; Up-Regulation</subject><ispartof>The Journal of biological chemistry, 2005-07, Vol.280 (26), p.25134-25145</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15802273$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Williams, Terence M</creatorcontrib><creatorcontrib>Hassan, Ghada S</creatorcontrib><creatorcontrib>Li, Jiangwei</creatorcontrib><creatorcontrib>Cohen, Alex W</creatorcontrib><creatorcontrib>Medina, Freddy</creatorcontrib><creatorcontrib>Frank, Philippe G</creatorcontrib><creatorcontrib>Pestell, Richard G</creatorcontrib><creatorcontrib>Di Vizio, Dolores</creatorcontrib><creatorcontrib>Loda, Massimo</creatorcontrib><creatorcontrib>Lisanti, Michael P</creatorcontrib><title>Caveolin-1 promotes tumor progression in an autochthonous mouse model of prostate cancer: genetic ablation of Cav-1 delays advanced prostate tumor development in tramp mice</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Caveolin-1 (Cav-1) is the primary structural component of caveolae and is implicated in the processes of vesicular transport, cholesterol balance, transformation, and tumorigenesis. Despite an abundance of data suggesting that Cav-1 has transformation suppressor properties both in vitro and in vivo, Cav-1 is expressed at increased levels in human prostate cancer. To investigate the role of Cav-1 in prostate cancer onset and progression, we interbred Cav-1(-/-) null mice with a TRAMP (transgenic adenocarcinoma of mouse prostate) model that spontaneously develops advanced prostate cancer and metastatic disease. We found that, although the loss of Cav-1 did not affect the appearance of minimally invasive prostate cancer, its absence significantly impeded progression to highly invasive and metastatic disease. Inactivation of one (+/-) or both (-/-) alleles of Cav-1 resulted in significant reductions in prostate tumor burden, as well as decreases in regional lymph node metastases. Moreover, further examination revealed decreased metastasis to distant organs, such as the lungs, in TRAMP/Cav-1(-/-) mice. Utilizing prostate carcinoma cell lines (C1, C2, and C3) derived from TRAMP tumors, we also showed a positive correlation between Cav-1 expression and the ability of these cells to form tumors in vivo. Furthermore, down-regulation of Cav-1 expression in these cells, using a small interfering RNA approach, significantly reduced their tumorigenic and metastatic potential. Mechanistically, we showed that loss or down-regulation of Cav-1 expression results in increased apoptosis, with increased prostate apoptosis response factor-4 and PTEN levels in Cav-1(-/-) null prostate tumors. Our current findings provide the first in vivo molecular genetic evidence that Cav-1 does indeed function as a tumor promoter during prostate carcinogenesis, rather than as a tumor suppressor.</description><subject>Animals</subject><subject>Antigens, Polyomavirus Transforming - chemistry</subject><subject>Apoptosis</subject><subject>Caveolin 1</subject><subject>Caveolins - metabolism</subject><subject>Caveolins - physiology</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cell Transformation, Neoplastic</subject><subject>Disease Models, Animal</subject><subject>Disease Progression</subject><subject>Down-Regulation</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genetic Vectors</subject><subject>Immunohistochemistry</subject><subject>In Situ Nick-End Labeling</subject><subject>Lymphatic Metastasis</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Neoplasm Metastasis</subject><subject>Neoplasms - pathology</subject><subject>Proliferating Cell Nuclear Antigen - metabolism</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Up-Regulation</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkEtPwzAMxyMEYmNw5Yhy4taRVx_hhiZe0hAXkLhNaeJunZqmNOmkfSc-JKk2hGXZsvSz_7YRuqZkTkku7ralnr-lhNIiY4ScoCklBU94Sr9O0ZQQRhPJ0mKCLrzfkmhC0nM0oWlBGMv5FP0s1A5cU7cJxV3vrAvgcRis68dy3YP3tWtx3WIVfQhOb8LGtW7w2MYAMRposKtG3AcVAGvVaujv8RpaCLXGqmxUGIdEKKpFodih9h4rsxtR8996EDawg8Z1FtowCode2Q7bWsMlOqtU4-HqmGfo8-nxY_GSLN-fXxcPy6RjgoSkksZQLhVPmVRAU20YY7IoSEornkOZiSpjIERJVF5mOWfCSAGZIYpmZV5pPkO3h7lxse8BfFjZ2mtoGtVCPHpF84xJztII3hzBobRgVl1fW9XvV3__5b-tmoD1</recordid><startdate>20050701</startdate><enddate>20050701</enddate><creator>Williams, Terence M</creator><creator>Hassan, Ghada S</creator><creator>Li, Jiangwei</creator><creator>Cohen, Alex W</creator><creator>Medina, Freddy</creator><creator>Frank, Philippe G</creator><creator>Pestell, Richard G</creator><creator>Di Vizio, Dolores</creator><creator>Loda, Massimo</creator><creator>Lisanti, Michael P</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20050701</creationdate><title>Caveolin-1 promotes tumor progression in an autochthonous mouse model of prostate cancer: genetic ablation of Cav-1 delays advanced prostate tumor development in tramp mice</title><author>Williams, Terence M ; Hassan, Ghada S ; Li, Jiangwei ; Cohen, Alex W ; Medina, Freddy ; Frank, Philippe G ; Pestell, Richard G ; Di Vizio, Dolores ; Loda, Massimo ; Lisanti, Michael P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p240t-f9dd139a3529ae15cd222988051f37eb64f62e44b0a7b67324d94e6d0a16b7fc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Antigens, Polyomavirus Transforming - chemistry</topic><topic>Apoptosis</topic><topic>Caveolin 1</topic><topic>Caveolins - metabolism</topic><topic>Caveolins - physiology</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Cell Transformation, Neoplastic</topic><topic>Disease Models, Animal</topic><topic>Disease Progression</topic><topic>Down-Regulation</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genetic Vectors</topic><topic>Immunohistochemistry</topic><topic>In Situ Nick-End Labeling</topic><topic>Lymphatic Metastasis</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Neoplasm Metastasis</topic><topic>Neoplasms - pathology</topic><topic>Proliferating Cell Nuclear Antigen - metabolism</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Williams, Terence M</creatorcontrib><creatorcontrib>Hassan, Ghada S</creatorcontrib><creatorcontrib>Li, Jiangwei</creatorcontrib><creatorcontrib>Cohen, Alex W</creatorcontrib><creatorcontrib>Medina, Freddy</creatorcontrib><creatorcontrib>Frank, Philippe G</creatorcontrib><creatorcontrib>Pestell, Richard G</creatorcontrib><creatorcontrib>Di Vizio, Dolores</creatorcontrib><creatorcontrib>Loda, Massimo</creatorcontrib><creatorcontrib>Lisanti, Michael P</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Williams, Terence M</au><au>Hassan, Ghada S</au><au>Li, Jiangwei</au><au>Cohen, Alex W</au><au>Medina, Freddy</au><au>Frank, Philippe G</au><au>Pestell, Richard G</au><au>Di Vizio, Dolores</au><au>Loda, Massimo</au><au>Lisanti, Michael P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Caveolin-1 promotes tumor progression in an autochthonous mouse model of prostate cancer: genetic ablation of Cav-1 delays advanced prostate tumor development in tramp mice</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2005-07-01</date><risdate>2005</risdate><volume>280</volume><issue>26</issue><spage>25134</spage><epage>25145</epage><pages>25134-25145</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Caveolin-1 (Cav-1) is the primary structural component of caveolae and is implicated in the processes of vesicular transport, cholesterol balance, transformation, and tumorigenesis. Despite an abundance of data suggesting that Cav-1 has transformation suppressor properties both in vitro and in vivo, Cav-1 is expressed at increased levels in human prostate cancer. To investigate the role of Cav-1 in prostate cancer onset and progression, we interbred Cav-1(-/-) null mice with a TRAMP (transgenic adenocarcinoma of mouse prostate) model that spontaneously develops advanced prostate cancer and metastatic disease. We found that, although the loss of Cav-1 did not affect the appearance of minimally invasive prostate cancer, its absence significantly impeded progression to highly invasive and metastatic disease. Inactivation of one (+/-) or both (-/-) alleles of Cav-1 resulted in significant reductions in prostate tumor burden, as well as decreases in regional lymph node metastases. Moreover, further examination revealed decreased metastasis to distant organs, such as the lungs, in TRAMP/Cav-1(-/-) mice. Utilizing prostate carcinoma cell lines (C1, C2, and C3) derived from TRAMP tumors, we also showed a positive correlation between Cav-1 expression and the ability of these cells to form tumors in vivo. Furthermore, down-regulation of Cav-1 expression in these cells, using a small interfering RNA approach, significantly reduced their tumorigenic and metastatic potential. Mechanistically, we showed that loss or down-regulation of Cav-1 expression results in increased apoptosis, with increased prostate apoptosis response factor-4 and PTEN levels in Cav-1(-/-) null prostate tumors. Our current findings provide the first in vivo molecular genetic evidence that Cav-1 does indeed function as a tumor promoter during prostate carcinogenesis, rather than as a tumor suppressor.</abstract><cop>United States</cop><pmid>15802273</pmid><doi>10.1074/jbc.M501186200</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antigens, Polyomavirus Transforming - chemistry Apoptosis Caveolin 1 Caveolins - metabolism Caveolins - physiology Cell Line Cell Line, Tumor Cell Transformation, Neoplastic Disease Models, Animal Disease Progression Down-Regulation Gene Expression Regulation, Neoplastic Genetic Vectors Immunohistochemistry In Situ Nick-End Labeling Lymphatic Metastasis Male Mice Mice, Inbred C57BL Mice, Transgenic Neoplasm Metastasis Neoplasms - pathology Proliferating Cell Nuclear Antigen - metabolism Prostatic Neoplasms - metabolism RNA, Small Interfering - metabolism Up-Regulation |
| title | Caveolin-1 promotes tumor progression in an autochthonous mouse model of prostate cancer: genetic ablation of Cav-1 delays advanced prostate tumor development in tramp mice |
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