Upregulation of scavenger receptor B1 is required for steroidogenic and non-steroidogenic cholesterol metabolism in prostate cancer
Identifieur interne : 000291 ( Main/Exploration ); précédent : 000290; suivant : 000292Upregulation of scavenger receptor B1 is required for steroidogenic and non-steroidogenic cholesterol metabolism in prostate cancer
Auteurs : Jacob A. Gordon [Canada] ; Jake W. Noble [Canada] ; Ankur Midha [Allemagne] ; Fatemeh Derakhshan [Canada] ; Gang Wang [Canada] ; Hans H. Adomat [Canada] ; Emma S. Tomlinson Guns [Canada] ; Yen-Yi Lin [Canada] ; Shancheng Ren [République populaire de Chine] ; Collin C. Collins [Canada] ; Peter S. Nelson [États-Unis] ; Colm Morrissey [États-Unis] ; Kishor M. Wasan [Canada] ; Michael E. Cox [Canada]Source :
- Cancer research [ 0008-5472 ] ; 2019.
Abstract
Aberrant cholesterol metabolism is increasingly appreciated to be essential for prostate cancer (PCa) initiation and progression. Transcript expression of the high-density lipoprotein-cholesterol receptor scavenger receptor B1 (SR-B1) is elevated in primary PCa. Hypothesizing that SR-B1 expression may help facilitate malignant transformation, we document increased SR-B1 protein and transcript expression in PCa relative to normal prostate epithelium that persists in lethal castration-resistant prostate cancer (CRPC) metastasis. As intratumoral steroid synthesis from the precursor cholesterol can drive androgen receptor (AR) pathway activity in CRPC, we screened androgenic benign and cancer cell lines for sensitivity to SR-B1 antagonism. Benign cells were insensitive to SR-B1 antagonism, and cancer line sensitivity inversely correlated with expression levels of full-length and splice-variant AR. In androgen-responsive CRPC cell model C4-2, SR-B1 antagonism suppressed cholesterol uptake, de novo steroidogenesis, and AR activity. SR-B1 antagonism also suppressed growth and viability and induced endoplasmic reticulum stress and autophagy. The inability of exogenous steroids to reverse these effects indicates that AR pathway activation is insufficient to overcome cytotoxic stress caused by a decrease in the availability of cholesterol. Furthermore, SR-B1 antagonism decreased cholesterol uptake, growth, and viability of the AR-null CRPC cell model PC-3, and the small molecule SR-BI antagonist Block Lipid Transport-1 decreased xenograft growth rate despite poor pharmacologic properties. Overall, our findings show that SR-B1 is upregulated in primary and castration-resistant disease and is essential for cholesterol uptake needed to drive both steroidogenic and non-steroidogenic biogenic pathways, thus implicating SR-B1 as a novel and potentially actionable target in CRPC.
Url:
DOI: 10.1158/0008-5472.CAN-18-2529
PubMed: 31064850
PubMed Central: 6606386
Affiliations:
- Allemagne, Canada, République populaire de Chine, États-Unis
- Berlin, Washington (État)
- Berlin, Seattle
- Université de Washington
Links toward previous steps (curation, corpus...)
- to stream Pmc, to step Corpus: 000388
- to stream Pmc, to step Curation: 000388
- to stream Pmc, to step Checkpoint: 000255
- to stream Ncbi, to step Merge: 000602
- to stream Ncbi, to step Curation: 000602
- to stream Ncbi, to step Checkpoint: 000602
- to stream Main, to step Merge: 000291
- to stream Main, to step Curation: 000291
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Upregulation of scavenger receptor B1 is required for steroidogenic and non-steroidogenic cholesterol metabolism in prostate cancer</title>
<author><name sortKey="Gordon, Jacob A" sort="Gordon, Jacob A" uniqKey="Gordon J" first="Jacob A." last="Gordon">Jacob A. Gordon</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Noble, Jake W" sort="Noble, Jake W" uniqKey="Noble J" first="Jake W." last="Noble">Jake W. Noble</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Midha, Ankur" sort="Midha, Ankur" uniqKey="Midha A" first="Ankur" last="Midha">Ankur Midha</name>
<affiliation wicri:level="3"><nlm:aff id="A3">Institute of Immunology, Freie Universität Berlin, Berlin, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Immunology, Freie Universität Berlin, Berlin</wicri:regionArea>
<placeName><region type="land" nuts="3">Berlin</region>
<settlement type="city">Berlin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Derakhshan, Fatemeh" sort="Derakhshan, Fatemeh" uniqKey="Derakhshan F" first="Fatemeh" last="Derakhshan">Fatemeh Derakhshan</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Pathology, British Columbia Cancer Agency, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Pathology, British Columbia Cancer Agency, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Wang, Gang" sort="Wang, Gang" uniqKey="Wang G" first="Gang" last="Wang">Gang Wang</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Pathology, British Columbia Cancer Agency, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Pathology, British Columbia Cancer Agency, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Adomat, Hans H" sort="Adomat, Hans H" uniqKey="Adomat H" first="Hans H." last="Adomat">Hans H. Adomat</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Guns, Emma S Tomlinson" sort="Guns, Emma S Tomlinson" uniqKey="Guns E" first="Emma S. Tomlinson" last="Guns">Emma S. Tomlinson Guns</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Lin, Yen Yi" sort="Lin, Yen Yi" uniqKey="Lin Y" first="Yen-Yi" last="Lin">Yen-Yi Lin</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ren, Shancheng" sort="Ren, Shancheng" uniqKey="Ren S" first="Shancheng" last="Ren">Shancheng Ren</name>
<affiliation wicri:level="1"><nlm:aff id="A5">Department of Urology, Second Military Medical University, Shanghai, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Urology, Second Military Medical University, Shanghai</wicri:regionArea>
<wicri:noRegion>Shanghai</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Collins, Collin C" sort="Collins, Collin C" uniqKey="Collins C" first="Collin C." last="Collins">Collin C. Collins</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Nelson, Peter S" sort="Nelson, Peter S" uniqKey="Nelson P" first="Peter S." last="Nelson">Peter S. Nelson</name>
<affiliation wicri:level="1"><nlm:aff id="A6">Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle WA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle WA</wicri:regionArea>
<wicri:noRegion>Seattle WA</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Morrissey, Colm" sort="Morrissey, Colm" uniqKey="Morrissey C" first="Colm" last="Morrissey">Colm Morrissey</name>
<affiliation wicri:level="4"><nlm:aff id="A7">Department of Urology, University of Washington, Seattle, WA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Urology, University of Washington, Seattle, WA</wicri:regionArea>
<orgName type="university">Université de Washington</orgName>
<placeName><settlement type="city">Seattle</settlement>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Wasan, Kishor M" sort="Wasan, Kishor M" uniqKey="Wasan K" first="Kishor M." last="Wasan">Kishor M. Wasan</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A8">College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon</wicri:regionArea>
<wicri:noRegion>Saskatoon</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Cox, Michael E" sort="Cox, Michael E" uniqKey="Cox M" first="Michael E." last="Cox">Michael E. Cox</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A9">Department of Urologic Sciences, University of British Columbia, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Urologic Sciences, University of British Columbia</wicri:regionArea>
<wicri:noRegion>University of British Columbia</wicri:noRegion>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">31064850</idno>
<idno type="pmc">6606386</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606386</idno>
<idno type="RBID">PMC:6606386</idno>
<idno type="doi">10.1158/0008-5472.CAN-18-2529</idno>
<date when="2019">2019</date>
<idno type="wicri:Area/Pmc/Corpus">000388</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000388</idno>
<idno type="wicri:Area/Pmc/Curation">000388</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000388</idno>
<idno type="wicri:Area/Pmc/Checkpoint">000255</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000255</idno>
<idno type="wicri:Area/Ncbi/Merge">000602</idno>
<idno type="wicri:Area/Ncbi/Curation">000602</idno>
<idno type="wicri:Area/Ncbi/Checkpoint">000602</idno>
<idno type="wicri:doubleKey">0008-5472:2019:Gordon J:upregulation:of:scavenger</idno>
<idno type="wicri:Area/Main/Merge">000291</idno>
<idno type="wicri:Area/Main/Curation">000291</idno>
<idno type="wicri:Area/Main/Exploration">000291</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Upregulation of scavenger receptor B1 is required for steroidogenic and non-steroidogenic cholesterol metabolism in prostate cancer</title>
<author><name sortKey="Gordon, Jacob A" sort="Gordon, Jacob A" uniqKey="Gordon J" first="Jacob A." last="Gordon">Jacob A. Gordon</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Noble, Jake W" sort="Noble, Jake W" uniqKey="Noble J" first="Jake W." last="Noble">Jake W. Noble</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Midha, Ankur" sort="Midha, Ankur" uniqKey="Midha A" first="Ankur" last="Midha">Ankur Midha</name>
<affiliation wicri:level="3"><nlm:aff id="A3">Institute of Immunology, Freie Universität Berlin, Berlin, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Immunology, Freie Universität Berlin, Berlin</wicri:regionArea>
<placeName><region type="land" nuts="3">Berlin</region>
<settlement type="city">Berlin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Derakhshan, Fatemeh" sort="Derakhshan, Fatemeh" uniqKey="Derakhshan F" first="Fatemeh" last="Derakhshan">Fatemeh Derakhshan</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Pathology, British Columbia Cancer Agency, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Pathology, British Columbia Cancer Agency, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Wang, Gang" sort="Wang, Gang" uniqKey="Wang G" first="Gang" last="Wang">Gang Wang</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Pathology, British Columbia Cancer Agency, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Pathology, British Columbia Cancer Agency, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Adomat, Hans H" sort="Adomat, Hans H" uniqKey="Adomat H" first="Hans H." last="Adomat">Hans H. Adomat</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Guns, Emma S Tomlinson" sort="Guns, Emma S Tomlinson" uniqKey="Guns E" first="Emma S. Tomlinson" last="Guns">Emma S. Tomlinson Guns</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Lin, Yen Yi" sort="Lin, Yen Yi" uniqKey="Lin Y" first="Yen-Yi" last="Lin">Yen-Yi Lin</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ren, Shancheng" sort="Ren, Shancheng" uniqKey="Ren S" first="Shancheng" last="Ren">Shancheng Ren</name>
<affiliation wicri:level="1"><nlm:aff id="A5">Department of Urology, Second Military Medical University, Shanghai, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Urology, Second Military Medical University, Shanghai</wicri:regionArea>
<wicri:noRegion>Shanghai</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Collins, Collin C" sort="Collins, Collin C" uniqKey="Collins C" first="Collin C." last="Collins">Collin C. Collins</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Nelson, Peter S" sort="Nelson, Peter S" uniqKey="Nelson P" first="Peter S." last="Nelson">Peter S. Nelson</name>
<affiliation wicri:level="1"><nlm:aff id="A6">Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle WA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle WA</wicri:regionArea>
<wicri:noRegion>Seattle WA</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Morrissey, Colm" sort="Morrissey, Colm" uniqKey="Morrissey C" first="Colm" last="Morrissey">Colm Morrissey</name>
<affiliation wicri:level="4"><nlm:aff id="A7">Department of Urology, University of Washington, Seattle, WA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Urology, University of Washington, Seattle, WA</wicri:regionArea>
<orgName type="university">Université de Washington</orgName>
<placeName><settlement type="city">Seattle</settlement>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Wasan, Kishor M" sort="Wasan, Kishor M" uniqKey="Wasan K" first="Kishor M." last="Wasan">Kishor M. Wasan</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A8">College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon</wicri:regionArea>
<wicri:noRegion>Saskatoon</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Cox, Michael E" sort="Cox, Michael E" uniqKey="Cox M" first="Michael E." last="Cox">Michael E. Cox</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver</wicri:regionArea>
<wicri:noRegion>Vancouver</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A9">Department of Urologic Sciences, University of British Columbia, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Urologic Sciences, University of British Columbia</wicri:regionArea>
<wicri:noRegion>University of British Columbia</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">Cancer research</title>
<idno type="ISSN">0008-5472</idno>
<idno type="eISSN">1538-7445</idno>
<imprint><date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="P1">Aberrant cholesterol metabolism is increasingly appreciated to be essential for prostate cancer (PCa) initiation and progression. Transcript expression of the high-density lipoprotein-cholesterol receptor scavenger receptor B1 (SR-B1) is elevated in primary PCa. Hypothesizing that SR-B1 expression may help facilitate malignant transformation, we document increased SR-B1 protein and transcript expression in PCa relative to normal prostate epithelium that persists in lethal castration-resistant prostate cancer (CRPC) metastasis. As intratumoral steroid synthesis from the precursor cholesterol can drive androgen receptor (AR) pathway activity in CRPC, we screened androgenic benign and cancer cell lines for sensitivity to SR-B1 antagonism. Benign cells were insensitive to SR-B1 antagonism, and cancer line sensitivity inversely correlated with expression levels of full-length and splice-variant AR. In androgen-responsive CRPC cell model C4-2, SR-B1 antagonism suppressed cholesterol uptake, de novo steroidogenesis, and AR activity. SR-B1 antagonism also suppressed growth and viability and induced endoplasmic reticulum stress and autophagy. The inability of exogenous steroids to reverse these effects indicates that AR pathway activation is insufficient to overcome cytotoxic stress caused by a decrease in the availability of cholesterol. Furthermore, SR-B1 antagonism decreased cholesterol uptake, growth, and viability of the AR-null CRPC cell model PC-3, and the small molecule SR-BI antagonist Block Lipid Transport-1 decreased xenograft growth rate despite poor pharmacologic properties. Overall, our findings show that SR-B1 is upregulated in primary and castration-resistant disease and is essential for cholesterol uptake needed to drive both steroidogenic and non-steroidogenic biogenic pathways, thus implicating SR-B1 as a novel and potentially actionable target in CRPC.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>Allemagne</li>
<li>Canada</li>
<li>République populaire de Chine</li>
<li>États-Unis</li>
</country>
<region><li>Berlin</li>
<li>Washington (État)</li>
</region>
<settlement><li>Berlin</li>
<li>Seattle</li>
</settlement>
<orgName><li>Université de Washington</li>
</orgName>
</list>
<tree><country name="Canada"><noRegion><name sortKey="Gordon, Jacob A" sort="Gordon, Jacob A" uniqKey="Gordon J" first="Jacob A." last="Gordon">Jacob A. Gordon</name>
</noRegion>
<name sortKey="Adomat, Hans H" sort="Adomat, Hans H" uniqKey="Adomat H" first="Hans H." last="Adomat">Hans H. Adomat</name>
<name sortKey="Collins, Collin C" sort="Collins, Collin C" uniqKey="Collins C" first="Collin C." last="Collins">Collin C. Collins</name>
<name sortKey="Cox, Michael E" sort="Cox, Michael E" uniqKey="Cox M" first="Michael E." last="Cox">Michael E. Cox</name>
<name sortKey="Cox, Michael E" sort="Cox, Michael E" uniqKey="Cox M" first="Michael E." last="Cox">Michael E. Cox</name>
<name sortKey="Cox, Michael E" sort="Cox, Michael E" uniqKey="Cox M" first="Michael E." last="Cox">Michael E. Cox</name>
<name sortKey="Derakhshan, Fatemeh" sort="Derakhshan, Fatemeh" uniqKey="Derakhshan F" first="Fatemeh" last="Derakhshan">Fatemeh Derakhshan</name>
<name sortKey="Gordon, Jacob A" sort="Gordon, Jacob A" uniqKey="Gordon J" first="Jacob A." last="Gordon">Jacob A. Gordon</name>
<name sortKey="Guns, Emma S Tomlinson" sort="Guns, Emma S Tomlinson" uniqKey="Guns E" first="Emma S. Tomlinson" last="Guns">Emma S. Tomlinson Guns</name>
<name sortKey="Guns, Emma S Tomlinson" sort="Guns, Emma S Tomlinson" uniqKey="Guns E" first="Emma S. Tomlinson" last="Guns">Emma S. Tomlinson Guns</name>
<name sortKey="Lin, Yen Yi" sort="Lin, Yen Yi" uniqKey="Lin Y" first="Yen-Yi" last="Lin">Yen-Yi Lin</name>
<name sortKey="Noble, Jake W" sort="Noble, Jake W" uniqKey="Noble J" first="Jake W." last="Noble">Jake W. Noble</name>
<name sortKey="Wang, Gang" sort="Wang, Gang" uniqKey="Wang G" first="Gang" last="Wang">Gang Wang</name>
<name sortKey="Wasan, Kishor M" sort="Wasan, Kishor M" uniqKey="Wasan K" first="Kishor M." last="Wasan">Kishor M. Wasan</name>
<name sortKey="Wasan, Kishor M" sort="Wasan, Kishor M" uniqKey="Wasan K" first="Kishor M." last="Wasan">Kishor M. Wasan</name>
</country>
<country name="Allemagne"><region name="Berlin"><name sortKey="Midha, Ankur" sort="Midha, Ankur" uniqKey="Midha A" first="Ankur" last="Midha">Ankur Midha</name>
</region>
</country>
<country name="République populaire de Chine"><noRegion><name sortKey="Ren, Shancheng" sort="Ren, Shancheng" uniqKey="Ren S" first="Shancheng" last="Ren">Shancheng Ren</name>
</noRegion>
</country>
<country name="États-Unis"><noRegion><name sortKey="Nelson, Peter S" sort="Nelson, Peter S" uniqKey="Nelson P" first="Peter S." last="Nelson">Peter S. Nelson</name>
</noRegion>
<name sortKey="Morrissey, Colm" sort="Morrissey, Colm" uniqKey="Morrissey C" first="Colm" last="Morrissey">Colm Morrissey</name>
</country>
</tree>
</affiliations>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/ChloroquineV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000291 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000291 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Sante |area= ChloroquineV1 |flux= Main |étape= Exploration |type= RBID |clé= PMC:6606386 |texte= Upregulation of scavenger receptor B1 is required for steroidogenic and non-steroidogenic cholesterol metabolism in prostate cancer }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:31064850" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \ | NlmPubMed2Wicri -a ChloroquineV1
This area was generated with Dilib version V0.6.33. |