Intratumoral conversion of adrenal androgen precursors drives androgen receptor-activated cell growth in prostate cancer more potently than de novo steroidogenesis

BACKGROUND Despite an initial response to hormonal therapy, patients with advanced prostate cancer (PC) almost always progress to castration‐resistant disease (CRPC). Although serum testosterone (T) is reduced by androgen deprivation therapy, intratumoral T levels in CRPC are comparable to those in...

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Veröffentlicht in:The Prostate 2013-11, Vol.73 (15), p.1636-1650
Hauptverfasser: Kumagai, Jinpei, Hofland, Johannes, Erkens-Schulze, Sigrun, Dits, Natasja F.J., Steenbergen, Jacobie, Jenster, Guido, Homma, Yukio, de Jong, Frank H., van Weerden, Wytske M.
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container_end_page 1650
container_issue 15
container_start_page 1636
container_title The Prostate
container_volume 73
creator Kumagai, Jinpei
Hofland, Johannes
Erkens-Schulze, Sigrun
Dits, Natasja F.J.
Steenbergen, Jacobie
Jenster, Guido
Homma, Yukio
de Jong, Frank H.
van Weerden, Wytske M.
description BACKGROUND Despite an initial response to hormonal therapy, patients with advanced prostate cancer (PC) almost always progress to castration‐resistant disease (CRPC). Although serum testosterone (T) is reduced by androgen deprivation therapy, intratumoral T levels in CRPC are comparable to those in prostate tissue of eugonadal men. These levels could originate from intratumoral conversion of adrenal androgens and/or from de novo steroid synthesis. However, the relative contribution of de novo steroidogenesis to AR‐driven cell growth is unknown. METHODS The relative contribution of androgen biosynthetic pathways to activate androgen receptor (AR)‐regulated cell growth and expression of PSA, FKBP5, and TMPRSS2 was studied at physiologically relevant levels of adrenal androgen precursors and intermediates of de novo androgen biosynthesis in human prostate cancer cell lines, PC346C, VCaP, and LNCaP. RESULTS In PC346C and VCaP, responses to pregnenolone and progesterone were absent or minimal, while large effects of adrenal androgen precursors were found. VCaP CRPC clones overexpressing CYP17A1 did not acquire an increased ability to use pregnenolone or progesterone to activate AR. In contrast, all precursors stimulated growth and gene expression in LNCaP cells, presumably resulting from the mutated AR in these cells. CONCLUSIONS Our data indicate that at physiological levels of T precursors PC cells can generally convert adrenal androgens, while de novo steroidogenesis is not generally possible in PC cells and is not able to support AR transactivation and PC growth. Prostate 73: 1636–1650, 2013. © 2013 Wiley Periodicals, Inc.
doi_str_mv 10.1002/pros.22655
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Although serum testosterone (T) is reduced by androgen deprivation therapy, intratumoral T levels in CRPC are comparable to those in prostate tissue of eugonadal men. These levels could originate from intratumoral conversion of adrenal androgens and/or from de novo steroid synthesis. However, the relative contribution of de novo steroidogenesis to AR‐driven cell growth is unknown. METHODS The relative contribution of androgen biosynthetic pathways to activate androgen receptor (AR)‐regulated cell growth and expression of PSA, FKBP5, and TMPRSS2 was studied at physiologically relevant levels of adrenal androgen precursors and intermediates of de novo androgen biosynthesis in human prostate cancer cell lines, PC346C, VCaP, and LNCaP. RESULTS In PC346C and VCaP, responses to pregnenolone and progesterone were absent or minimal, while large effects of adrenal androgen precursors were found. VCaP CRPC clones overexpressing CYP17A1 did not acquire an increased ability to use pregnenolone or progesterone to activate AR. In contrast, all precursors stimulated growth and gene expression in LNCaP cells, presumably resulting from the mutated AR in these cells. CONCLUSIONS Our data indicate that at physiological levels of T precursors PC cells can generally convert adrenal androgens, while de novo steroidogenesis is not generally possible in PC cells and is not able to support AR transactivation and PC growth. Prostate 73: 1636–1650, 2013. © 2013 Wiley Periodicals, Inc.</description><identifier>ISSN: 0270-4137</identifier><identifier>EISSN: 1097-0045</identifier><identifier>DOI: 10.1002/pros.22655</identifier><identifier>PMID: 23996639</identifier><identifier>CODEN: PRSTDS</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>androgen-independent prostate cancer ; androgen-responsive genes ; Androgens - biosynthesis ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Male ; precursors of testosterone ; proliferation ; Prostate - metabolism ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - metabolism ; Prostatic Neoplasms - pathology ; real-time RT-PCR ; Receptors, Androgen - metabolism ; Steroid 17-alpha-Hydroxylase - genetics ; Steroid 17-alpha-Hydroxylase - metabolism</subject><ispartof>The Prostate, 2013-11, Vol.73 (15), p.1636-1650</ispartof><rights>2013 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4265-3b898339091d0368a1cd9015845735bb30b99cbf5af4824d7b300beb1e2efba43</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fpros.22655$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fpros.22655$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23996639$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kumagai, Jinpei</creatorcontrib><creatorcontrib>Hofland, Johannes</creatorcontrib><creatorcontrib>Erkens-Schulze, Sigrun</creatorcontrib><creatorcontrib>Dits, Natasja F.J.</creatorcontrib><creatorcontrib>Steenbergen, Jacobie</creatorcontrib><creatorcontrib>Jenster, Guido</creatorcontrib><creatorcontrib>Homma, Yukio</creatorcontrib><creatorcontrib>de Jong, Frank H.</creatorcontrib><creatorcontrib>van Weerden, Wytske M.</creatorcontrib><title>Intratumoral conversion of adrenal androgen precursors drives androgen receptor-activated cell growth in prostate cancer more potently than de novo steroidogenesis</title><title>The Prostate</title><addtitle>Prostate</addtitle><description>BACKGROUND Despite an initial response to hormonal therapy, patients with advanced prostate cancer (PC) almost always progress to castration‐resistant disease (CRPC). Although serum testosterone (T) is reduced by androgen deprivation therapy, intratumoral T levels in CRPC are comparable to those in prostate tissue of eugonadal men. These levels could originate from intratumoral conversion of adrenal androgens and/or from de novo steroid synthesis. However, the relative contribution of de novo steroidogenesis to AR‐driven cell growth is unknown. METHODS The relative contribution of androgen biosynthetic pathways to activate androgen receptor (AR)‐regulated cell growth and expression of PSA, FKBP5, and TMPRSS2 was studied at physiologically relevant levels of adrenal androgen precursors and intermediates of de novo androgen biosynthesis in human prostate cancer cell lines, PC346C, VCaP, and LNCaP. RESULTS In PC346C and VCaP, responses to pregnenolone and progesterone were absent or minimal, while large effects of adrenal androgen precursors were found. VCaP CRPC clones overexpressing CYP17A1 did not acquire an increased ability to use pregnenolone or progesterone to activate AR. In contrast, all precursors stimulated growth and gene expression in LNCaP cells, presumably resulting from the mutated AR in these cells. CONCLUSIONS Our data indicate that at physiological levels of T precursors PC cells can generally convert adrenal androgens, while de novo steroidogenesis is not generally possible in PC cells and is not able to support AR transactivation and PC growth. Prostate 73: 1636–1650, 2013. © 2013 Wiley Periodicals, Inc.</description><subject>androgen-independent prostate cancer</subject><subject>androgen-responsive genes</subject><subject>Androgens - biosynthesis</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Humans</subject><subject>Male</subject><subject>precursors of testosterone</subject><subject>proliferation</subject><subject>Prostate - metabolism</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>Prostatic Neoplasms - pathology</subject><subject>real-time RT-PCR</subject><subject>Receptors, Androgen - metabolism</subject><subject>Steroid 17-alpha-Hydroxylase - genetics</subject><subject>Steroid 17-alpha-Hydroxylase - metabolism</subject><issn>0270-4137</issn><issn>1097-0045</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1u1DAUhS0EokPLhgdAltiwSeufJI6XqKI_UjVFhardWU5807pk7GA7U-Z5eNE6M6VIrGzd851r33MR-kDJISWEHY3Bx0PG6qp6hRaUSFEQUlav0YIwQYqScrGH3sX4QEjGCXuL9hiXsq65XKA_5y4FnaaVD3rAnXdrCNF6h32PtQngclU7E_wdODwG6KYQfYjYBLuG-E_KCozJh0J3ya51AoM7GAZ8F_xjusd2NvuYsoA77ToIOL8IePQJXBo2ON1rhw1g59cexwTBWzM3hmjjAXrT6yHC--dzH12ffP1xfFZcXJ6eH3-5KLoyD1_wtpEN55JIagivG007IwmtmrISvGpbTlopu7avdF82rDQiV0gLLQUGfatLvo8-7_rmr_6aICa1snGeQjvwU1S05E0l6prKjH76D33wU8hhbSnBmloIkamPz9TUrsCoMdiVDhv1N_4M0B3waAfYvOiUqHmxao5MbRervl1dft_esqfYeWyO6feLR4efqhZcVOpmear48nZ5IuiZuuJPGYipYg</recordid><startdate>201311</startdate><enddate>201311</enddate><creator>Kumagai, Jinpei</creator><creator>Hofland, Johannes</creator><creator>Erkens-Schulze, Sigrun</creator><creator>Dits, Natasja F.J.</creator><creator>Steenbergen, Jacobie</creator><creator>Jenster, Guido</creator><creator>Homma, Yukio</creator><creator>de Jong, Frank H.</creator><creator>van Weerden, Wytske M.</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7T5</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201311</creationdate><title>Intratumoral conversion of adrenal androgen precursors drives androgen receptor-activated cell growth in prostate cancer more potently than de novo steroidogenesis</title><author>Kumagai, Jinpei ; Hofland, Johannes ; Erkens-Schulze, Sigrun ; Dits, Natasja F.J. ; Steenbergen, Jacobie ; Jenster, Guido ; Homma, Yukio ; de Jong, Frank H. ; van Weerden, Wytske M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4265-3b898339091d0368a1cd9015845735bb30b99cbf5af4824d7b300beb1e2efba43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>androgen-independent prostate cancer</topic><topic>androgen-responsive genes</topic><topic>Androgens - biosynthesis</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Humans</topic><topic>Male</topic><topic>precursors of testosterone</topic><topic>proliferation</topic><topic>Prostate - metabolism</topic><topic>Prostatic Neoplasms - genetics</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>Prostatic Neoplasms - pathology</topic><topic>real-time RT-PCR</topic><topic>Receptors, Androgen - metabolism</topic><topic>Steroid 17-alpha-Hydroxylase - genetics</topic><topic>Steroid 17-alpha-Hydroxylase - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kumagai, Jinpei</creatorcontrib><creatorcontrib>Hofland, Johannes</creatorcontrib><creatorcontrib>Erkens-Schulze, Sigrun</creatorcontrib><creatorcontrib>Dits, Natasja F.J.</creatorcontrib><creatorcontrib>Steenbergen, Jacobie</creatorcontrib><creatorcontrib>Jenster, Guido</creatorcontrib><creatorcontrib>Homma, Yukio</creatorcontrib><creatorcontrib>de Jong, Frank H.</creatorcontrib><creatorcontrib>van Weerden, Wytske M.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Immunology Abstracts</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>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Prostate</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kumagai, Jinpei</au><au>Hofland, Johannes</au><au>Erkens-Schulze, Sigrun</au><au>Dits, Natasja F.J.</au><au>Steenbergen, Jacobie</au><au>Jenster, Guido</au><au>Homma, Yukio</au><au>de Jong, Frank H.</au><au>van Weerden, Wytske M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intratumoral conversion of adrenal androgen precursors drives androgen receptor-activated cell growth in prostate cancer more potently than de novo steroidogenesis</atitle><jtitle>The Prostate</jtitle><addtitle>Prostate</addtitle><date>2013-11</date><risdate>2013</risdate><volume>73</volume><issue>15</issue><spage>1636</spage><epage>1650</epage><pages>1636-1650</pages><issn>0270-4137</issn><eissn>1097-0045</eissn><coden>PRSTDS</coden><abstract>BACKGROUND Despite an initial response to hormonal therapy, patients with advanced prostate cancer (PC) almost always progress to castration‐resistant disease (CRPC). Although serum testosterone (T) is reduced by androgen deprivation therapy, intratumoral T levels in CRPC are comparable to those in prostate tissue of eugonadal men. These levels could originate from intratumoral conversion of adrenal androgens and/or from de novo steroid synthesis. However, the relative contribution of de novo steroidogenesis to AR‐driven cell growth is unknown. METHODS The relative contribution of androgen biosynthetic pathways to activate androgen receptor (AR)‐regulated cell growth and expression of PSA, FKBP5, and TMPRSS2 was studied at physiologically relevant levels of adrenal androgen precursors and intermediates of de novo androgen biosynthesis in human prostate cancer cell lines, PC346C, VCaP, and LNCaP. RESULTS In PC346C and VCaP, responses to pregnenolone and progesterone were absent or minimal, while large effects of adrenal androgen precursors were found. VCaP CRPC clones overexpressing CYP17A1 did not acquire an increased ability to use pregnenolone or progesterone to activate AR. In contrast, all precursors stimulated growth and gene expression in LNCaP cells, presumably resulting from the mutated AR in these cells. CONCLUSIONS Our data indicate that at physiological levels of T precursors PC cells can generally convert adrenal androgens, while de novo steroidogenesis is not generally possible in PC cells and is not able to support AR transactivation and PC growth. Prostate 73: 1636–1650, 2013. © 2013 Wiley Periodicals, Inc.</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>23996639</pmid><doi>10.1002/pros.22655</doi><tpages>15</tpages></addata></record>
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subjects androgen-independent prostate cancer
androgen-responsive genes
Androgens - biosynthesis
Cell Line, Tumor
Cell Proliferation
Humans
Male
precursors of testosterone
proliferation
Prostate - metabolism
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
real-time RT-PCR
Receptors, Androgen - metabolism
Steroid 17-alpha-Hydroxylase - genetics
Steroid 17-alpha-Hydroxylase - metabolism
title Intratumoral conversion of adrenal androgen precursors drives androgen receptor-activated cell growth in prostate cancer more potently than de novo steroidogenesis
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