Pioglitazone Inhibits Androgen Production in NCI-H295R Cells by Regulating Gene Expression of CYP17 and HSD3B2
Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone are widely used as insulin sensitizers in the treatment of type 2 diabetes. In diabetic women with polycystic ovary syndrome, treatment with pioglitazone or rosiglitazone improves insulin resistance and hyperandrogenism, but the mechan...
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| Veröffentlicht in: | Molecular pharmacology 2007-03, Vol.71 (3), p.787-798 |
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| creator | Kempna, Petra Hofer, Gaby Mullis, Primus E Flueck, Christa E |
| description | Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone are widely used as insulin sensitizers in the treatment of
type 2 diabetes. In diabetic women with polycystic ovary syndrome, treatment with pioglitazone or rosiglitazone improves insulin
resistance and hyperandrogenism, but the mechanism by which TZDs down-regulate androgen production is unknown. Androgens are
synthesized in the human gonads as well as the adrenals. We studied the regulation of androgen production by analyzing the
effect of pioglitazone and rosiglitazone on steroidogenesis in human adrenal NCI-H295R cells, an established in vitro model
of steroidogenesis of the human adrenal cortex. Both TZDs changed the steroid profile of the NCI-H295R cells and inhibited
the activities of P450c17 and 3βHSDII, key enzymes of androgen biosynthesis. Pioglitazone but not rosiglitazone inhibited
the expression of the CYP17 and HSD3B2 genes. Likewise, pioglitazone repressed basal and 8-bromo-cAMP-stimulated activities of CYP17 and HSD3B2 promoter reporters in NCI-H295R cells. However, pioglitazone did not change the activity of a cAMP-responsive luciferase
reporter, indicating that it does not influence cAMP/protein kinase A/cAMP response element-binding protein pathway signaling.
Although peroxisome proliferator-activated receptor γ (PPARγ) is the nuclear receptor for TZDs, suppression of PPARγ by small
interfering RNA technique did not alter the inhibitory effect of pioglitazone on CYP17 and HSD3B2 expression, suggesting that the action of pioglitazone is independent of PPARγ. On the other hand, treatment of NCI-H295R
cells with mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor 2-(2-amino-3-methoxyphenyl)-4 H -1-benzopyran-4-one (PD98059) enhanced promoter activity and expression of CYP17 . This effect was reversed by pioglitazone treatment, indicating that the MEK/ERK signaling pathway plays a role in regulating
androgen biosynthesis by pioglitazone. |
| doi_str_mv | 10.1124/mol.106.028902 |
| format | Article |
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type 2 diabetes. In diabetic women with polycystic ovary syndrome, treatment with pioglitazone or rosiglitazone improves insulin
resistance and hyperandrogenism, but the mechanism by which TZDs down-regulate androgen production is unknown. Androgens are
synthesized in the human gonads as well as the adrenals. We studied the regulation of androgen production by analyzing the
effect of pioglitazone and rosiglitazone on steroidogenesis in human adrenal NCI-H295R cells, an established in vitro model
of steroidogenesis of the human adrenal cortex. Both TZDs changed the steroid profile of the NCI-H295R cells and inhibited
the activities of P450c17 and 3βHSDII, key enzymes of androgen biosynthesis. Pioglitazone but not rosiglitazone inhibited
the expression of the CYP17 and HSD3B2 genes. Likewise, pioglitazone repressed basal and 8-bromo-cAMP-stimulated activities of CYP17 and HSD3B2 promoter reporters in NCI-H295R cells. However, pioglitazone did not change the activity of a cAMP-responsive luciferase
reporter, indicating that it does not influence cAMP/protein kinase A/cAMP response element-binding protein pathway signaling.
Although peroxisome proliferator-activated receptor γ (PPARγ) is the nuclear receptor for TZDs, suppression of PPARγ by small
interfering RNA technique did not alter the inhibitory effect of pioglitazone on CYP17 and HSD3B2 expression, suggesting that the action of pioglitazone is independent of PPARγ. On the other hand, treatment of NCI-H295R
cells with mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor 2-(2-amino-3-methoxyphenyl)-4 H -1-benzopyran-4-one (PD98059) enhanced promoter activity and expression of CYP17 . This effect was reversed by pioglitazone treatment, indicating that the MEK/ERK signaling pathway plays a role in regulating
androgen biosynthesis by pioglitazone.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>DOI: 10.1124/mol.106.028902</identifier><identifier>PMID: 17138841</identifier><language>eng</language><publisher>United States: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>3-Hydroxysteroid Dehydrogenases - genetics ; Adrenal Glands - metabolism ; Androgens - biosynthesis ; Base Sequence ; Cells, Cultured ; Cyclic AMP - physiology ; Cyclic AMP Response Element-Binding Protein - physiology ; Cyclic AMP-Dependent Protein Kinases - physiology ; Extracellular Signal-Regulated MAP Kinases - physiology ; Gene Expression Regulation, Enzymologic - drug effects ; Humans ; Hypoglycemic Agents - pharmacology ; Molecular Sequence Data ; PPAR gamma - physiology ; Promoter Regions, Genetic ; RNA, Messenger - analysis ; Steroid 17-alpha-Hydroxylase - genetics ; Thiazolidinediones - pharmacology</subject><ispartof>Molecular pharmacology, 2007-03, Vol.71 (3), p.787-798</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c354t-854ef8e4c3514291a405a48c394061dd0ce192ffb18dfdef1c85ab980fd289d33</citedby><cites>FETCH-LOGICAL-c354t-854ef8e4c3514291a405a48c394061dd0ce192ffb18dfdef1c85ab980fd289d33</cites></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/17138841$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kempna, Petra</creatorcontrib><creatorcontrib>Hofer, Gaby</creatorcontrib><creatorcontrib>Mullis, Primus E</creatorcontrib><creatorcontrib>Flueck, Christa E</creatorcontrib><title>Pioglitazone Inhibits Androgen Production in NCI-H295R Cells by Regulating Gene Expression of CYP17 and HSD3B2</title><title>Molecular pharmacology</title><addtitle>Mol Pharmacol</addtitle><description>Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone are widely used as insulin sensitizers in the treatment of
type 2 diabetes. In diabetic women with polycystic ovary syndrome, treatment with pioglitazone or rosiglitazone improves insulin
resistance and hyperandrogenism, but the mechanism by which TZDs down-regulate androgen production is unknown. Androgens are
synthesized in the human gonads as well as the adrenals. We studied the regulation of androgen production by analyzing the
effect of pioglitazone and rosiglitazone on steroidogenesis in human adrenal NCI-H295R cells, an established in vitro model
of steroidogenesis of the human adrenal cortex. Both TZDs changed the steroid profile of the NCI-H295R cells and inhibited
the activities of P450c17 and 3βHSDII, key enzymes of androgen biosynthesis. Pioglitazone but not rosiglitazone inhibited
the expression of the CYP17 and HSD3B2 genes. Likewise, pioglitazone repressed basal and 8-bromo-cAMP-stimulated activities of CYP17 and HSD3B2 promoter reporters in NCI-H295R cells. However, pioglitazone did not change the activity of a cAMP-responsive luciferase
reporter, indicating that it does not influence cAMP/protein kinase A/cAMP response element-binding protein pathway signaling.
Although peroxisome proliferator-activated receptor γ (PPARγ) is the nuclear receptor for TZDs, suppression of PPARγ by small
interfering RNA technique did not alter the inhibitory effect of pioglitazone on CYP17 and HSD3B2 expression, suggesting that the action of pioglitazone is independent of PPARγ. On the other hand, treatment of NCI-H295R
cells with mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor 2-(2-amino-3-methoxyphenyl)-4 H -1-benzopyran-4-one (PD98059) enhanced promoter activity and expression of CYP17 . This effect was reversed by pioglitazone treatment, indicating that the MEK/ERK signaling pathway plays a role in regulating
androgen biosynthesis by pioglitazone.</description><subject>3-Hydroxysteroid Dehydrogenases - genetics</subject><subject>Adrenal Glands - metabolism</subject><subject>Androgens - biosynthesis</subject><subject>Base Sequence</subject><subject>Cells, Cultured</subject><subject>Cyclic AMP - physiology</subject><subject>Cyclic AMP Response Element-Binding Protein - physiology</subject><subject>Cyclic AMP-Dependent Protein Kinases - physiology</subject><subject>Extracellular Signal-Regulated MAP Kinases - physiology</subject><subject>Gene Expression Regulation, Enzymologic - drug effects</subject><subject>Humans</subject><subject>Hypoglycemic Agents - pharmacology</subject><subject>Molecular Sequence Data</subject><subject>PPAR gamma - physiology</subject><subject>Promoter Regions, Genetic</subject><subject>RNA, Messenger - analysis</subject><subject>Steroid 17-alpha-Hydroxylase - genetics</subject><subject>Thiazolidinediones - pharmacology</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUFv1DAQhS0EokvhyhH5ArcsHsdOnGMJpbtSBasCEpwsJ7azRom92Ilg--vralfiyGlmpO89jd5D6DWQNQBl76cwroFUa0JFQ-gTtAJOoSAA8BStCKFVIRr-4wK9SOkXIcC4IM_RBdRQCsFghfzOhWF0s7oP3uCt37vOzQlfeR3DYDzexaCXfnbBY-fx53ZbbGjD73BrxjHh7ojvzLCManZ-wDcmW1z_PUST0qMgWNz-3EGNldd48_Vj-YG-RM-sGpN5dZ6X6Pun62_tprj9crNtr26LvuRsLgRnxgrD8gWMNqAY4YqJvmwYqUBr0htoqLUdCG21sdALrrpGEKtzDrosL9G7k-8hht-LSbOcXOrzz8qbsCRZ5bBoVbH_gtDkX3hdZ3B9AvsYUorGykN0k4pHCUQ-ViFzFXmv5KmKLHhzdl66yeh_-Dn7DLw9AXs37P-4aORhr-Kk-jCG4ShrkKWsRV0-AFErj_A</recordid><startdate>20070301</startdate><enddate>20070301</enddate><creator>Kempna, Petra</creator><creator>Hofer, Gaby</creator><creator>Mullis, Primus E</creator><creator>Flueck, Christa E</creator><general>American Society for Pharmacology and Experimental Therapeutics</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>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20070301</creationdate><title>Pioglitazone Inhibits Androgen Production in NCI-H295R Cells by Regulating Gene Expression of CYP17 and HSD3B2</title><author>Kempna, Petra ; Hofer, Gaby ; Mullis, Primus E ; Flueck, Christa E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c354t-854ef8e4c3514291a405a48c394061dd0ce192ffb18dfdef1c85ab980fd289d33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>3-Hydroxysteroid Dehydrogenases - genetics</topic><topic>Adrenal Glands - metabolism</topic><topic>Androgens - biosynthesis</topic><topic>Base Sequence</topic><topic>Cells, Cultured</topic><topic>Cyclic AMP - physiology</topic><topic>Cyclic AMP Response Element-Binding Protein - physiology</topic><topic>Cyclic AMP-Dependent Protein Kinases - physiology</topic><topic>Extracellular Signal-Regulated MAP Kinases - physiology</topic><topic>Gene Expression Regulation, Enzymologic - drug effects</topic><topic>Humans</topic><topic>Hypoglycemic Agents - pharmacology</topic><topic>Molecular Sequence Data</topic><topic>PPAR gamma - physiology</topic><topic>Promoter Regions, Genetic</topic><topic>RNA, Messenger - analysis</topic><topic>Steroid 17-alpha-Hydroxylase - genetics</topic><topic>Thiazolidinediones - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kempna, Petra</creatorcontrib><creatorcontrib>Hofer, Gaby</creatorcontrib><creatorcontrib>Mullis, Primus E</creatorcontrib><creatorcontrib>Flueck, Christa E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kempna, Petra</au><au>Hofer, Gaby</au><au>Mullis, Primus E</au><au>Flueck, Christa E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pioglitazone Inhibits Androgen Production in NCI-H295R Cells by Regulating Gene Expression of CYP17 and HSD3B2</atitle><jtitle>Molecular pharmacology</jtitle><addtitle>Mol Pharmacol</addtitle><date>2007-03-01</date><risdate>2007</risdate><volume>71</volume><issue>3</issue><spage>787</spage><epage>798</epage><pages>787-798</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><abstract>Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone are widely used as insulin sensitizers in the treatment of
type 2 diabetes. In diabetic women with polycystic ovary syndrome, treatment with pioglitazone or rosiglitazone improves insulin
resistance and hyperandrogenism, but the mechanism by which TZDs down-regulate androgen production is unknown. Androgens are
synthesized in the human gonads as well as the adrenals. We studied the regulation of androgen production by analyzing the
effect of pioglitazone and rosiglitazone on steroidogenesis in human adrenal NCI-H295R cells, an established in vitro model
of steroidogenesis of the human adrenal cortex. Both TZDs changed the steroid profile of the NCI-H295R cells and inhibited
the activities of P450c17 and 3βHSDII, key enzymes of androgen biosynthesis. Pioglitazone but not rosiglitazone inhibited
the expression of the CYP17 and HSD3B2 genes. Likewise, pioglitazone repressed basal and 8-bromo-cAMP-stimulated activities of CYP17 and HSD3B2 promoter reporters in NCI-H295R cells. However, pioglitazone did not change the activity of a cAMP-responsive luciferase
reporter, indicating that it does not influence cAMP/protein kinase A/cAMP response element-binding protein pathway signaling.
Although peroxisome proliferator-activated receptor γ (PPARγ) is the nuclear receptor for TZDs, suppression of PPARγ by small
interfering RNA technique did not alter the inhibitory effect of pioglitazone on CYP17 and HSD3B2 expression, suggesting that the action of pioglitazone is independent of PPARγ. On the other hand, treatment of NCI-H295R
cells with mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor 2-(2-amino-3-methoxyphenyl)-4 H -1-benzopyran-4-one (PD98059) enhanced promoter activity and expression of CYP17 . This effect was reversed by pioglitazone treatment, indicating that the MEK/ERK signaling pathway plays a role in regulating
androgen biosynthesis by pioglitazone.</abstract><cop>United States</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>17138841</pmid><doi>10.1124/mol.106.028902</doi><tpages>12</tpages></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Free Full-Text Journals in Chemistry |
| subjects | 3-Hydroxysteroid Dehydrogenases - genetics Adrenal Glands - metabolism Androgens - biosynthesis Base Sequence Cells, Cultured Cyclic AMP - physiology Cyclic AMP Response Element-Binding Protein - physiology Cyclic AMP-Dependent Protein Kinases - physiology Extracellular Signal-Regulated MAP Kinases - physiology Gene Expression Regulation, Enzymologic - drug effects Humans Hypoglycemic Agents - pharmacology Molecular Sequence Data PPAR gamma - physiology Promoter Regions, Genetic RNA, Messenger - analysis Steroid 17-alpha-Hydroxylase - genetics Thiazolidinediones - pharmacology |
| title | Pioglitazone Inhibits Androgen Production in NCI-H295R Cells by Regulating Gene Expression of CYP17 and HSD3B2 |
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