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Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer
Plasma and tumor caveolin-1 (Cav-1) are linked with disease progression in prostate cancer. Here we report that metabolomic profiling of longitudinal plasmas from a prospective cohort of 491 active surveillance (AS) participants indicates prominent elevations in plasma sphingolipids in AS progressor...
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| Published in: | Nature communications 2020-08, Vol.11 (1), p.4279-4279, Article 4279 |
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| creator | Vykoukal, Jody Fahrmann, Johannes F. Gregg, Justin R. Tang, Zhe Basourakos, Spyridon Irajizad, Ehsan Park, Sanghee Yang, Guang Creighton, Chad J. Fleury, Alia Mayo, Jeffrey Paulucci-Holthauzen, Adriana Dennison, Jennifer B. Murage, Eunice Peterson, Christine B. Davis, John W. Kim, Jeri Hanash, Samir Thompson, Timothy C. |
| description | Plasma and tumor caveolin-1 (Cav-1) are linked with disease progression in prostate cancer. Here we report that metabolomic profiling of longitudinal plasmas from a prospective cohort of 491 active surveillance (AS) participants indicates prominent elevations in plasma sphingolipids in AS progressors that, together with plasma Cav-1, yield a prognostic signature for disease progression. Mechanistic studies of the underlying tumor supportive onco-metabolism reveal coordinated activities through which Cav-1 enables rewiring of cancer cell lipid metabolism towards a program of 1) exogenous sphingolipid scavenging independent of cholesterol, 2) increased cancer cell catabolism of sphingomyelins to ceramide derivatives and 3) altered ceramide metabolism that results in increased glycosphingolipid synthesis and efflux of Cav-1-sphingolipid particles containing mitochondrial proteins and lipids. We also demonstrate, using a prostate cancer syngeneic RM-9 mouse model and established cell lines, that this Cav-1-sphingolipid program evidences a metabolic vulnerability that is targetable to induce lethal mitophagy as an anti-tumor therapy.
The mechanisms associated with Caveolin-1 (Cav-1) mediated metabolic changes in prostate cancer are unclear. Here, the authors show that Cav-1 promotes rewiring of cancer cell lipid metabolism towards a program of exogenous lipid scavenging and vesicle biogenesis that intersects with mitochondrial dynamics in prostate tumors. |
| doi_str_mv | 10.1038/s41467-020-17645-z |
| format | article |
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The mechanisms associated with Caveolin-1 (Cav-1) mediated metabolic changes in prostate cancer are unclear. Here, the authors show that Cav-1 promotes rewiring of cancer cell lipid metabolism towards a program of exogenous lipid scavenging and vesicle biogenesis that intersects with mitochondrial dynamics in prostate tumors.</description><identifier>ISSN: 2041-1723</identifier><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/s41467-020-17645-z</identifier><identifier>PMID: 32855410</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/106 ; 13/109 ; 13/51 ; 13/89 ; 14/19 ; 140/58 ; 631/45 ; 631/67 ; 631/80 ; 64/60 ; 82/16 ; 96/34 ; Catabolism ; Caveolin ; Caveolin-1 ; Ceramide ; Cholesterol ; Efflux ; Humanities and Social Sciences ; Lipid metabolism ; Lipids ; Metabolism ; Metabolomics ; Mitochondria ; multidisciplinary ; Plasmas (physics) ; Prostate cancer ; Rewiring ; Scavenging ; Science ; Science (multidisciplinary) ; Sphingolipids ; Tumors</subject><ispartof>Nature communications, 2020-08, Vol.11 (1), p.4279-4279, Article 4279</ispartof><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c517t-880472338452e6a06dabbbe5c65f9cc2a9486825ebf5bf9fe0a4aae66222ef53</citedby><cites>FETCH-LOGICAL-c517t-880472338452e6a06dabbbe5c65f9cc2a9486825ebf5bf9fe0a4aae66222ef53</cites><orcidid>0000-0002-6090-703X ; 0000-0002-8532-8712 ; 0000-0003-3316-0468 ; 0000-0002-4210-1593 ; 0000-0003-1424-3831</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2437639716/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2437639716?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,25731,27901,27902,36989,36990,44566,53766,53768,74869</link.rule.ids></links><search><creatorcontrib>Vykoukal, Jody</creatorcontrib><creatorcontrib>Fahrmann, Johannes F.</creatorcontrib><creatorcontrib>Gregg, Justin R.</creatorcontrib><creatorcontrib>Tang, Zhe</creatorcontrib><creatorcontrib>Basourakos, Spyridon</creatorcontrib><creatorcontrib>Irajizad, Ehsan</creatorcontrib><creatorcontrib>Park, Sanghee</creatorcontrib><creatorcontrib>Yang, Guang</creatorcontrib><creatorcontrib>Creighton, Chad J.</creatorcontrib><creatorcontrib>Fleury, Alia</creatorcontrib><creatorcontrib>Mayo, Jeffrey</creatorcontrib><creatorcontrib>Paulucci-Holthauzen, Adriana</creatorcontrib><creatorcontrib>Dennison, Jennifer B.</creatorcontrib><creatorcontrib>Murage, Eunice</creatorcontrib><creatorcontrib>Peterson, Christine B.</creatorcontrib><creatorcontrib>Davis, John W.</creatorcontrib><creatorcontrib>Kim, Jeri</creatorcontrib><creatorcontrib>Hanash, Samir</creatorcontrib><creatorcontrib>Thompson, Timothy C.</creatorcontrib><title>Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><description>Plasma and tumor caveolin-1 (Cav-1) are linked with disease progression in prostate cancer. Here we report that metabolomic profiling of longitudinal plasmas from a prospective cohort of 491 active surveillance (AS) participants indicates prominent elevations in plasma sphingolipids in AS progressors that, together with plasma Cav-1, yield a prognostic signature for disease progression. Mechanistic studies of the underlying tumor supportive onco-metabolism reveal coordinated activities through which Cav-1 enables rewiring of cancer cell lipid metabolism towards a program of 1) exogenous sphingolipid scavenging independent of cholesterol, 2) increased cancer cell catabolism of sphingomyelins to ceramide derivatives and 3) altered ceramide metabolism that results in increased glycosphingolipid synthesis and efflux of Cav-1-sphingolipid particles containing mitochondrial proteins and lipids. We also demonstrate, using a prostate cancer syngeneic RM-9 mouse model and established cell lines, that this Cav-1-sphingolipid program evidences a metabolic vulnerability that is targetable to induce lethal mitophagy as an anti-tumor therapy.
The mechanisms associated with Caveolin-1 (Cav-1) mediated metabolic changes in prostate cancer are unclear. Here, the authors show that Cav-1 promotes rewiring of cancer cell lipid metabolism towards a program of exogenous lipid scavenging and vesicle biogenesis that intersects with mitochondrial dynamics in prostate tumors.</description><subject>13/106</subject><subject>13/109</subject><subject>13/51</subject><subject>13/89</subject><subject>14/19</subject><subject>140/58</subject><subject>631/45</subject><subject>631/67</subject><subject>631/80</subject><subject>64/60</subject><subject>82/16</subject><subject>96/34</subject><subject>Catabolism</subject><subject>Caveolin</subject><subject>Caveolin-1</subject><subject>Ceramide</subject><subject>Cholesterol</subject><subject>Efflux</subject><subject>Humanities and Social Sciences</subject><subject>Lipid metabolism</subject><subject>Lipids</subject><subject>Metabolism</subject><subject>Metabolomics</subject><subject>Mitochondria</subject><subject>multidisciplinary</subject><subject>Plasmas (physics)</subject><subject>Prostate 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Jeffrey</au><au>Paulucci-Holthauzen, Adriana</au><au>Dennison, Jennifer B.</au><au>Murage, Eunice</au><au>Peterson, Christine B.</au><au>Davis, John W.</au><au>Kim, Jeri</au><au>Hanash, Samir</au><au>Thompson, Timothy C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer</atitle><jtitle>Nature communications</jtitle><stitle>Nat Commun</stitle><date>2020-08-27</date><risdate>2020</risdate><volume>11</volume><issue>1</issue><spage>4279</spage><epage>4279</epage><pages>4279-4279</pages><artnum>4279</artnum><issn>2041-1723</issn><eissn>2041-1723</eissn><abstract>Plasma and tumor caveolin-1 (Cav-1) are linked with disease progression in prostate cancer. Here we report that metabolomic profiling of longitudinal plasmas from a prospective cohort of 491 active surveillance (AS) participants indicates prominent elevations in plasma sphingolipids in AS progressors that, together with plasma Cav-1, yield a prognostic signature for disease progression. Mechanistic studies of the underlying tumor supportive onco-metabolism reveal coordinated activities through which Cav-1 enables rewiring of cancer cell lipid metabolism towards a program of 1) exogenous sphingolipid scavenging independent of cholesterol, 2) increased cancer cell catabolism of sphingomyelins to ceramide derivatives and 3) altered ceramide metabolism that results in increased glycosphingolipid synthesis and efflux of Cav-1-sphingolipid particles containing mitochondrial proteins and lipids. We also demonstrate, using a prostate cancer syngeneic RM-9 mouse model and established cell lines, that this Cav-1-sphingolipid program evidences a metabolic vulnerability that is targetable to induce lethal mitophagy as an anti-tumor therapy.
The mechanisms associated with Caveolin-1 (Cav-1) mediated metabolic changes in prostate cancer are unclear. Here, the authors show that Cav-1 promotes rewiring of cancer cell lipid metabolism towards a program of exogenous lipid scavenging and vesicle biogenesis that intersects with mitochondrial dynamics in prostate tumors.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32855410</pmid><doi>10.1038/s41467-020-17645-z</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-6090-703X</orcidid><orcidid>https://orcid.org/0000-0002-8532-8712</orcidid><orcidid>https://orcid.org/0000-0003-3316-0468</orcidid><orcidid>https://orcid.org/0000-0002-4210-1593</orcidid><orcidid>https://orcid.org/0000-0003-1424-3831</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13/106 13/109 13/51 13/89 14/19 140/58 631/45 631/67 631/80 64/60 82/16 96/34 Catabolism Caveolin Caveolin-1 Ceramide Cholesterol Efflux Humanities and Social Sciences Lipid metabolism Lipids Metabolism Metabolomics Mitochondria multidisciplinary Plasmas (physics) Prostate cancer Rewiring Scavenging Science Science (multidisciplinary) Sphingolipids Tumors |
| title | Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-30T19%3A05%3A40IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_doaj_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Caveolin-1-mediated%20sphingolipid%20oncometabolism%20underlies%20a%20metabolic%20vulnerability%20of%20prostate%20cancer&rft.jtitle=Nature%20communications&rft.au=Vykoukal,%20Jody&rft.date=2020-08-27&rft.volume=11&rft.issue=1&rft.spage=4279&rft.epage=4279&rft.pages=4279-4279&rft.artnum=4279&rft.issn=2041-1723&rft.eissn=2041-1723&rft_id=info:doi/10.1038/s41467-020-17645-z&rft_dat=%3Cproquest_doaj_%3E2437639716%3C/proquest_doaj_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c517t-880472338452e6a06dabbbe5c65f9cc2a9486825ebf5bf9fe0a4aae66222ef53%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2437639716&rft_id=info:pmid/32855410&rfr_iscdi=true |