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Essential Role of Caveolae in Interleukin-6- and Insulin-like Growth Factor I-triggered Akt-1-mediated Survival of Multiple Myeloma Cells
Caveolae, specialized flask-shaped lipid rafts on the cell surface, are composed of cholesterol, sphingolipids, and structural proteins termed caveolins; functionally, these plasma membrane microdomains have been implicated in signal transduction and transmembrane transport. In the present study, we...
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| Published in: | The Journal of biological chemistry 2003-02, Vol.278 (8), p.5794-5801 |
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| creator | Podar, Klaus Tai, Yu-Tzu Cole, Craig E Hideshima, Teru Sattler, Martin Hamblin, Angela Mitsiades, Nicholas Schlossman, Robert L Davies, Faith E Morgan, Gareth J Munshi, Nikhil C Chauhan, Dharminder Anderson, Kenneth C |
| description | Caveolae, specialized flask-shaped lipid rafts on the cell surface, are composed of cholesterol, sphingolipids, and structural
proteins termed caveolins; functionally, these plasma membrane microdomains have been implicated in signal transduction and
transmembrane transport. In the present study, we examined the role of caveolin-1 in multiple myeloma cells. We show for the
first time that caveolin-1, which is usually absent in blood cells, is expressed in multiple myeloma cells. Analysis of myeloma
cell-derived plasma membrane fractions shows that caveolin-1 is co-localized with interleukin-6 receptor signal transducing
chain gp130 and with insulin-like growth factor-I receptor. Cholesterol depletion by β-cyclodextrin results in the loss of
caveola structure in myeloma cells, as shown by transmission electron microscopy, and loss of caveolin-1 function. Interleukin-6
and insulin-like growth factor-I, growth and survival factors in multiple myeloma, induce caveolin-1 phosphorylation, which
is abrogated by pre-treatment with β-cyclodextrin. Importantly, inhibition of caveolin-1 phosphorylation blocks both interleukin-6-induced
protein complex formation with caveolin-1 and downstream activation of the phosphatidylinositol 3-kinase/Akt-1 pathway. β-Cyclodextrin
also blocks insulin-like growth factor-I-induced tyrosine phosphorylation of insulin-responsive substrate-1 and downstream
activation of the phosphatidylinositol 3-kinase/Akt-1 pathway. Therefore, cholesterol depletion by β-cyclodextrin abrogates
both interleukin-6- and insulin-like growth factor-I-triggered multiple myeloma cell survival via negative regulation of caveolin-1.
Taken together, this study identifies caveolin-1 and other structural membrane components as potential new therapeutic targets
in multiple myeloma. |
| doi_str_mv | 10.1074/jbc.M208636200 |
| format | article |
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proteins termed caveolins; functionally, these plasma membrane microdomains have been implicated in signal transduction and
transmembrane transport. In the present study, we examined the role of caveolin-1 in multiple myeloma cells. We show for the
first time that caveolin-1, which is usually absent in blood cells, is expressed in multiple myeloma cells. Analysis of myeloma
cell-derived plasma membrane fractions shows that caveolin-1 is co-localized with interleukin-6 receptor signal transducing
chain gp130 and with insulin-like growth factor-I receptor. Cholesterol depletion by β-cyclodextrin results in the loss of
caveola structure in myeloma cells, as shown by transmission electron microscopy, and loss of caveolin-1 function. Interleukin-6
and insulin-like growth factor-I, growth and survival factors in multiple myeloma, induce caveolin-1 phosphorylation, which
is abrogated by pre-treatment with β-cyclodextrin. Importantly, inhibition of caveolin-1 phosphorylation blocks both interleukin-6-induced
protein complex formation with caveolin-1 and downstream activation of the phosphatidylinositol 3-kinase/Akt-1 pathway. β-Cyclodextrin
also blocks insulin-like growth factor-I-induced tyrosine phosphorylation of insulin-responsive substrate-1 and downstream
activation of the phosphatidylinositol 3-kinase/Akt-1 pathway. Therefore, cholesterol depletion by β-cyclodextrin abrogates
both interleukin-6- and insulin-like growth factor-I-triggered multiple myeloma cell survival via negative regulation of caveolin-1.
Taken together, this study identifies caveolin-1 and other structural membrane components as potential new therapeutic targets
in multiple myeloma.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M208636200</identifier><identifier>PMID: 12482878</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Caveolae - drug effects ; Caveolae - immunology ; Caveolae - physiology ; Cell Survival - drug effects ; Cell Survival - immunology ; Cell Survival - physiology ; Cholesterol - metabolism ; Humans ; Insulin-Like Growth Factor I - pharmacology ; Interleukin-6 - pharmacology ; Multiple Myeloma - pathology ; Protein-Serine-Threonine Kinases - metabolism ; Proto-Oncogene Proteins ; Proto-Oncogene Proteins c-akt ; Recombinant Proteins - pharmacology ; Signal Transduction - drug effects ; Tumor Cells, Cultured</subject><ispartof>The Journal of biological chemistry, 2003-02, Vol.278 (8), p.5794-5801</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c500t-55de2afbb32bc57aba5d55edea56bbdb7792b3a1b3c33390c593dae99a17b5663</citedby><cites>FETCH-LOGICAL-c500t-55de2afbb32bc57aba5d55edea56bbdb7792b3a1b3c33390c593dae99a17b5663</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12482878$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Podar, Klaus</creatorcontrib><creatorcontrib>Tai, Yu-Tzu</creatorcontrib><creatorcontrib>Cole, Craig E</creatorcontrib><creatorcontrib>Hideshima, Teru</creatorcontrib><creatorcontrib>Sattler, Martin</creatorcontrib><creatorcontrib>Hamblin, Angela</creatorcontrib><creatorcontrib>Mitsiades, Nicholas</creatorcontrib><creatorcontrib>Schlossman, Robert L</creatorcontrib><creatorcontrib>Davies, Faith E</creatorcontrib><creatorcontrib>Morgan, Gareth J</creatorcontrib><creatorcontrib>Munshi, Nikhil C</creatorcontrib><creatorcontrib>Chauhan, Dharminder</creatorcontrib><creatorcontrib>Anderson, Kenneth C</creatorcontrib><title>Essential Role of Caveolae in Interleukin-6- and Insulin-like Growth Factor I-triggered Akt-1-mediated Survival of Multiple Myeloma Cells</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Caveolae, specialized flask-shaped lipid rafts on the cell surface, are composed of cholesterol, sphingolipids, and structural
proteins termed caveolins; functionally, these plasma membrane microdomains have been implicated in signal transduction and
transmembrane transport. In the present study, we examined the role of caveolin-1 in multiple myeloma cells. We show for the
first time that caveolin-1, which is usually absent in blood cells, is expressed in multiple myeloma cells. Analysis of myeloma
cell-derived plasma membrane fractions shows that caveolin-1 is co-localized with interleukin-6 receptor signal transducing
chain gp130 and with insulin-like growth factor-I receptor. Cholesterol depletion by β-cyclodextrin results in the loss of
caveola structure in myeloma cells, as shown by transmission electron microscopy, and loss of caveolin-1 function. Interleukin-6
and insulin-like growth factor-I, growth and survival factors in multiple myeloma, induce caveolin-1 phosphorylation, which
is abrogated by pre-treatment with β-cyclodextrin. Importantly, inhibition of caveolin-1 phosphorylation blocks both interleukin-6-induced
protein complex formation with caveolin-1 and downstream activation of the phosphatidylinositol 3-kinase/Akt-1 pathway. β-Cyclodextrin
also blocks insulin-like growth factor-I-induced tyrosine phosphorylation of insulin-responsive substrate-1 and downstream
activation of the phosphatidylinositol 3-kinase/Akt-1 pathway. Therefore, cholesterol depletion by β-cyclodextrin abrogates
both interleukin-6- and insulin-like growth factor-I-triggered multiple myeloma cell survival via negative regulation of caveolin-1.
Taken together, this study identifies caveolin-1 and other structural membrane components as potential new therapeutic targets
in multiple myeloma.</description><subject>Caveolae - drug effects</subject><subject>Caveolae - immunology</subject><subject>Caveolae - physiology</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - immunology</subject><subject>Cell Survival - physiology</subject><subject>Cholesterol - metabolism</subject><subject>Humans</subject><subject>Insulin-Like Growth Factor I - pharmacology</subject><subject>Interleukin-6 - pharmacology</subject><subject>Multiple Myeloma - pathology</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins</subject><subject>Proto-Oncogene Proteins c-akt</subject><subject>Recombinant Proteins - pharmacology</subject><subject>Signal Transduction - drug effects</subject><subject>Tumor Cells, Cultured</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><recordid>eNqFkU1rGzEQhkVpaRy31x6L6CE3ufpY7WqPwSSpIabQD-hNSLtjW7F25Upah_yE_usq2JBj5jLM8My8w7wIfWJ0wWhTfX2w3WLNqapFzSl9g2aMKkGEZH_eohmlnJGWS3WBLlN6oCWqlr1HF4xXiqtGzdC_m5RgzM54_CN4wGGDl-YIwRvAbsSrMUP0MO3dSGqCzdiXVpp8Kb3bA76L4THv8K3pcoh4RXJ02y1E6PH1PhNGBuidyaX8OcWjOxaVIrCefHaHIrZ-Ah8Gg5fgffqA3m2MT_DxnOfo9-3Nr-U3cv_9brW8viedpDQTKXvgZmOt4LaTjbFG9lJCD0bW1va2aVpuhWFWdEKIlnayFb2BtjWssbKuxRxdnfYeYvg7Qcp6cKkrF5gRwpR0I6igjaheBZmqFX-m52hxArsYUoqw0YfoBhOfNKP62SVdXNIvLpWBz-fNky0fesHPthTgywnYue3u0UXQ1oVuB4PmjdJKy6atxH95QZps</recordid><startdate>20030221</startdate><enddate>20030221</enddate><creator>Podar, Klaus</creator><creator>Tai, Yu-Tzu</creator><creator>Cole, Craig E</creator><creator>Hideshima, Teru</creator><creator>Sattler, Martin</creator><creator>Hamblin, Angela</creator><creator>Mitsiades, Nicholas</creator><creator>Schlossman, Robert L</creator><creator>Davies, Faith E</creator><creator>Morgan, Gareth J</creator><creator>Munshi, Nikhil C</creator><creator>Chauhan, Dharminder</creator><creator>Anderson, Kenneth C</creator><general>American Society for Biochemistry and Molecular Biology</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>7TO</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20030221</creationdate><title>Essential Role of Caveolae in Interleukin-6- and Insulin-like Growth Factor I-triggered Akt-1-mediated Survival of Multiple Myeloma Cells</title><author>Podar, Klaus ; Tai, Yu-Tzu ; Cole, Craig E ; Hideshima, Teru ; Sattler, Martin ; Hamblin, Angela ; Mitsiades, Nicholas ; Schlossman, Robert L ; Davies, Faith E ; Morgan, Gareth J ; Munshi, Nikhil C ; Chauhan, Dharminder ; Anderson, Kenneth C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c500t-55de2afbb32bc57aba5d55edea56bbdb7792b3a1b3c33390c593dae99a17b5663</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Caveolae - drug effects</topic><topic>Caveolae - immunology</topic><topic>Caveolae - physiology</topic><topic>Cell Survival - drug effects</topic><topic>Cell Survival - immunology</topic><topic>Cell Survival - physiology</topic><topic>Cholesterol - metabolism</topic><topic>Humans</topic><topic>Insulin-Like Growth Factor I - pharmacology</topic><topic>Interleukin-6 - pharmacology</topic><topic>Multiple Myeloma - pathology</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Proto-Oncogene Proteins</topic><topic>Proto-Oncogene Proteins c-akt</topic><topic>Recombinant Proteins - pharmacology</topic><topic>Signal Transduction - drug effects</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Podar, Klaus</creatorcontrib><creatorcontrib>Tai, Yu-Tzu</creatorcontrib><creatorcontrib>Cole, Craig E</creatorcontrib><creatorcontrib>Hideshima, Teru</creatorcontrib><creatorcontrib>Sattler, Martin</creatorcontrib><creatorcontrib>Hamblin, Angela</creatorcontrib><creatorcontrib>Mitsiades, Nicholas</creatorcontrib><creatorcontrib>Schlossman, Robert L</creatorcontrib><creatorcontrib>Davies, Faith E</creatorcontrib><creatorcontrib>Morgan, Gareth J</creatorcontrib><creatorcontrib>Munshi, Nikhil C</creatorcontrib><creatorcontrib>Chauhan, Dharminder</creatorcontrib><creatorcontrib>Anderson, Kenneth C</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Podar, Klaus</au><au>Tai, Yu-Tzu</au><au>Cole, Craig E</au><au>Hideshima, Teru</au><au>Sattler, Martin</au><au>Hamblin, Angela</au><au>Mitsiades, Nicholas</au><au>Schlossman, Robert L</au><au>Davies, Faith E</au><au>Morgan, Gareth J</au><au>Munshi, Nikhil C</au><au>Chauhan, Dharminder</au><au>Anderson, Kenneth C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Essential Role of Caveolae in Interleukin-6- and Insulin-like Growth Factor I-triggered Akt-1-mediated Survival of Multiple Myeloma Cells</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2003-02-21</date><risdate>2003</risdate><volume>278</volume><issue>8</issue><spage>5794</spage><epage>5801</epage><pages>5794-5801</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Caveolae, specialized flask-shaped lipid rafts on the cell surface, are composed of cholesterol, sphingolipids, and structural
proteins termed caveolins; functionally, these plasma membrane microdomains have been implicated in signal transduction and
transmembrane transport. In the present study, we examined the role of caveolin-1 in multiple myeloma cells. We show for the
first time that caveolin-1, which is usually absent in blood cells, is expressed in multiple myeloma cells. Analysis of myeloma
cell-derived plasma membrane fractions shows that caveolin-1 is co-localized with interleukin-6 receptor signal transducing
chain gp130 and with insulin-like growth factor-I receptor. Cholesterol depletion by β-cyclodextrin results in the loss of
caveola structure in myeloma cells, as shown by transmission electron microscopy, and loss of caveolin-1 function. Interleukin-6
and insulin-like growth factor-I, growth and survival factors in multiple myeloma, induce caveolin-1 phosphorylation, which
is abrogated by pre-treatment with β-cyclodextrin. Importantly, inhibition of caveolin-1 phosphorylation blocks both interleukin-6-induced
protein complex formation with caveolin-1 and downstream activation of the phosphatidylinositol 3-kinase/Akt-1 pathway. β-Cyclodextrin
also blocks insulin-like growth factor-I-induced tyrosine phosphorylation of insulin-responsive substrate-1 and downstream
activation of the phosphatidylinositol 3-kinase/Akt-1 pathway. Therefore, cholesterol depletion by β-cyclodextrin abrogates
both interleukin-6- and insulin-like growth factor-I-triggered multiple myeloma cell survival via negative regulation of caveolin-1.
Taken together, this study identifies caveolin-1 and other structural membrane components as potential new therapeutic targets
in multiple myeloma.</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>12482878</pmid><doi>10.1074/jbc.M208636200</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | ScienceDirect Additional Titles |
| subjects | Caveolae - drug effects Caveolae - immunology Caveolae - physiology Cell Survival - drug effects Cell Survival - immunology Cell Survival - physiology Cholesterol - metabolism Humans Insulin-Like Growth Factor I - pharmacology Interleukin-6 - pharmacology Multiple Myeloma - pathology Protein-Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins Proto-Oncogene Proteins c-akt Recombinant Proteins - pharmacology Signal Transduction - drug effects Tumor Cells, Cultured |
| title | Essential Role of Caveolae in Interleukin-6- and Insulin-like Growth Factor I-triggered Akt-1-mediated Survival of Multiple Myeloma Cells |
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