Demethylating Reagent 5-Azacytidine Inhibits Telomerase Activity in Human Prostate Cancer Cells through Transcriptional Repression of hTERT
Telomerase activation is thought to be a critical step in cellular immortality and oncogenesis. Several reagents including differentiation-inducing and antineoplastic agents are known to inhibit telomerase activity, although the molecular mechanisms through which they inhibit telomerase activity rem...
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| Veröffentlicht in: | Clinical cancer research 2000-07, Vol.6 (7), p.2868-2875 |
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| creator | KITAGAWA, Y KYO, S TAKAKURA, M KANAYA, T KOSHIDA, K NAMIKI, M INOUE, M |
| description | Telomerase
activation is thought to be a critical step in cellular immortality and
oncogenesis. Several reagents including differentiation-inducing and
antineoplastic agents are known to inhibit telomerase activity,
although the molecular mechanisms through which they inhibit telomerase
activity remain unclear. Demethylating reagents have recently been used
as potential antineoplastic drugs for some types of cancers including
those of the prostate. In the present study, we examined the effect of
the demethylating reagent 5-azacytidine (5-aza-CR) on telomerase
activity using cells of two prostate cancer cell lines, DU-145 and
TSU-PR1. 5-aza-CR treatment significantly reduced telomerase activity
in TSU-PR1 cells, but not in DU-145 cells, although growth inhibition
was observed to a similar extent in both cell lines. Reverse
transcription-PCR analyses revealed that inhibition of telomerase
activity was accompanied by down-regulation of telomerase catalytic
subunit (hTERT) mRNA expression. Transient expression assays showed
that 5-aza-CR repressed the transcriptional activity of the hTERT
promoter and that the E-box within the core promoter was responsible
for this down-regulation. Western blot analyses revealed that 5-aza-CR
reactivated p16 expression and repressed c-Myc expression in
TSU-PR1 cells but not in DU-145 cells. Overexpression of p16 in TSU-PR1
cells led to significant repression of c- Myc
transcription. These findings suggest that 5-aza-CR inhibits telomerase
activity via transcriptional repression of hTERT , in
which p16 and c-Myc may play a key role. |
| format | Article |
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activation is thought to be a critical step in cellular immortality and
oncogenesis. Several reagents including differentiation-inducing and
antineoplastic agents are known to inhibit telomerase activity,
although the molecular mechanisms through which they inhibit telomerase
activity remain unclear. Demethylating reagents have recently been used
as potential antineoplastic drugs for some types of cancers including
those of the prostate. In the present study, we examined the effect of
the demethylating reagent 5-azacytidine (5-aza-CR) on telomerase
activity using cells of two prostate cancer cell lines, DU-145 and
TSU-PR1. 5-aza-CR treatment significantly reduced telomerase activity
in TSU-PR1 cells, but not in DU-145 cells, although growth inhibition
was observed to a similar extent in both cell lines. Reverse
transcription-PCR analyses revealed that inhibition of telomerase
activity was accompanied by down-regulation of telomerase catalytic
subunit (hTERT) mRNA expression. Transient expression assays showed
that 5-aza-CR repressed the transcriptional activity of the hTERT
promoter and that the E-box within the core promoter was responsible
for this down-regulation. Western blot analyses revealed that 5-aza-CR
reactivated p16 expression and repressed c-Myc expression in
TSU-PR1 cells but not in DU-145 cells. Overexpression of p16 in TSU-PR1
cells led to significant repression of c- Myc
transcription. These findings suggest that 5-aza-CR inhibits telomerase
activity via transcriptional repression of hTERT , in
which p16 and c-Myc may play a key role.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>PMID: 10914736</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Antineoplastic agents ; Azacitidine - pharmacology ; Biological and medical sciences ; Catalytic Domain ; Chemotherapy ; DNA-Binding Proteins ; Gene Expression Regulation, Neoplastic - drug effects ; Genes, Reporter ; Humans ; Luciferases - genetics ; Male ; Medical sciences ; Pharmacology. Drug treatments ; Prostatic Neoplasms - enzymology ; Prostatic Neoplasms - genetics ; RNA ; Telomerase - antagonists & inhibitors ; Telomerase - genetics ; Transcription, Genetic - drug effects ; Transfection ; Tumor Cells, Cultured</subject><ispartof>Clinical cancer research, 2000-07, Vol.6 (7), p.2868-2875</ispartof><rights>2000 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1464908$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10914736$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>KITAGAWA, Y</creatorcontrib><creatorcontrib>KYO, S</creatorcontrib><creatorcontrib>TAKAKURA, M</creatorcontrib><creatorcontrib>KANAYA, T</creatorcontrib><creatorcontrib>KOSHIDA, K</creatorcontrib><creatorcontrib>NAMIKI, M</creatorcontrib><creatorcontrib>INOUE, M</creatorcontrib><title>Demethylating Reagent 5-Azacytidine Inhibits Telomerase Activity in Human Prostate Cancer Cells through Transcriptional Repression of hTERT</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Telomerase
activation is thought to be a critical step in cellular immortality and
oncogenesis. Several reagents including differentiation-inducing and
antineoplastic agents are known to inhibit telomerase activity,
although the molecular mechanisms through which they inhibit telomerase
activity remain unclear. Demethylating reagents have recently been used
as potential antineoplastic drugs for some types of cancers including
those of the prostate. In the present study, we examined the effect of
the demethylating reagent 5-azacytidine (5-aza-CR) on telomerase
activity using cells of two prostate cancer cell lines, DU-145 and
TSU-PR1. 5-aza-CR treatment significantly reduced telomerase activity
in TSU-PR1 cells, but not in DU-145 cells, although growth inhibition
was observed to a similar extent in both cell lines. Reverse
transcription-PCR analyses revealed that inhibition of telomerase
activity was accompanied by down-regulation of telomerase catalytic
subunit (hTERT) mRNA expression. Transient expression assays showed
that 5-aza-CR repressed the transcriptional activity of the hTERT
promoter and that the E-box within the core promoter was responsible
for this down-regulation. Western blot analyses revealed that 5-aza-CR
reactivated p16 expression and repressed c-Myc expression in
TSU-PR1 cells but not in DU-145 cells. Overexpression of p16 in TSU-PR1
cells led to significant repression of c- Myc
transcription. These findings suggest that 5-aza-CR inhibits telomerase
activity via transcriptional repression of hTERT , in
which p16 and c-Myc may play a key role.</description><subject>Antineoplastic agents</subject><subject>Azacitidine - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Catalytic Domain</subject><subject>Chemotherapy</subject><subject>DNA-Binding Proteins</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Genes, Reporter</subject><subject>Humans</subject><subject>Luciferases - genetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Prostatic Neoplasms - enzymology</subject><subject>Prostatic Neoplasms - genetics</subject><subject>RNA</subject><subject>Telomerase - antagonists & inhibitors</subject><subject>Telomerase - genetics</subject><subject>Transcription, Genetic - drug effects</subject><subject>Transfection</subject><subject>Tumor Cells, Cultured</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkNtKxDAQhosonl9BciF6VUiTtE0vl_UIgiL1ukzT6SbSpmuSKusr-NIGXfFqZuBjZv5vJznM8rxMOSvy3djTUqZUcHaQHHn_SmkmMir2k4OMVpkoeXGYfF3hiEFvBgjGrsgzwgptIHm6-AS1CaYzFsm91aY1wZMah2lEBx7JQgXzbsKGGEvu5hEseXKTDxCQLMEqdGSJw-BJ0G6aV5rUDqxXzqyDmSwM8dLaofdxIFNPdH39XJ8kez0MHk-39Th5ubmul3fpw-Pt_XLxkGpWyJDKlhYoJMuRAa1y0fE2xmqFAtn2QvaKdqKDPi84payiXDKh-i4DXrESsAd-nFz87l276W1GH5rReBW_BYvT7JsyY3lWChHBsy04tyN2zdqZEdym-dMXgfMtAF7B0MeMyvh_ThSiojJil7-YNiv9YRw26kdRFIDglG6KpmyYLCT_BgxKiZg</recordid><startdate>20000701</startdate><enddate>20000701</enddate><creator>KITAGAWA, Y</creator><creator>KYO, S</creator><creator>TAKAKURA, M</creator><creator>KANAYA, T</creator><creator>KOSHIDA, K</creator><creator>NAMIKI, M</creator><creator>INOUE, M</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20000701</creationdate><title>Demethylating Reagent 5-Azacytidine Inhibits Telomerase Activity in Human Prostate Cancer Cells through Transcriptional Repression of hTERT</title><author>KITAGAWA, Y ; KYO, S ; TAKAKURA, M ; KANAYA, T ; KOSHIDA, K ; NAMIKI, M ; INOUE, M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h268t-8b06e4825e2a0954d3b410b4ca8bf48fc0d4daf563002903824cfd1a3927aefa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Antineoplastic agents</topic><topic>Azacitidine - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Catalytic Domain</topic><topic>Chemotherapy</topic><topic>DNA-Binding Proteins</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Genes, Reporter</topic><topic>Humans</topic><topic>Luciferases - genetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Prostatic Neoplasms - enzymology</topic><topic>Prostatic Neoplasms - genetics</topic><topic>RNA</topic><topic>Telomerase - antagonists & inhibitors</topic><topic>Telomerase - genetics</topic><topic>Transcription, Genetic - drug effects</topic><topic>Transfection</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>KITAGAWA, Y</creatorcontrib><creatorcontrib>KYO, S</creatorcontrib><creatorcontrib>TAKAKURA, M</creatorcontrib><creatorcontrib>KANAYA, T</creatorcontrib><creatorcontrib>KOSHIDA, K</creatorcontrib><creatorcontrib>NAMIKI, M</creatorcontrib><creatorcontrib>INOUE, M</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>KITAGAWA, Y</au><au>KYO, S</au><au>TAKAKURA, M</au><au>KANAYA, T</au><au>KOSHIDA, K</au><au>NAMIKI, M</au><au>INOUE, M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Demethylating Reagent 5-Azacytidine Inhibits Telomerase Activity in Human Prostate Cancer Cells through Transcriptional Repression of hTERT</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2000-07-01</date><risdate>2000</risdate><volume>6</volume><issue>7</issue><spage>2868</spage><epage>2875</epage><pages>2868-2875</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Telomerase
activation is thought to be a critical step in cellular immortality and
oncogenesis. Several reagents including differentiation-inducing and
antineoplastic agents are known to inhibit telomerase activity,
although the molecular mechanisms through which they inhibit telomerase
activity remain unclear. Demethylating reagents have recently been used
as potential antineoplastic drugs for some types of cancers including
those of the prostate. In the present study, we examined the effect of
the demethylating reagent 5-azacytidine (5-aza-CR) on telomerase
activity using cells of two prostate cancer cell lines, DU-145 and
TSU-PR1. 5-aza-CR treatment significantly reduced telomerase activity
in TSU-PR1 cells, but not in DU-145 cells, although growth inhibition
was observed to a similar extent in both cell lines. Reverse
transcription-PCR analyses revealed that inhibition of telomerase
activity was accompanied by down-regulation of telomerase catalytic
subunit (hTERT) mRNA expression. Transient expression assays showed
that 5-aza-CR repressed the transcriptional activity of the hTERT
promoter and that the E-box within the core promoter was responsible
for this down-regulation. Western blot analyses revealed that 5-aza-CR
reactivated p16 expression and repressed c-Myc expression in
TSU-PR1 cells but not in DU-145 cells. Overexpression of p16 in TSU-PR1
cells led to significant repression of c- Myc
transcription. These findings suggest that 5-aza-CR inhibits telomerase
activity via transcriptional repression of hTERT , in
which p16 and c-Myc may play a key role.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>10914736</pmid><tpages>8</tpages></addata></record> |
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| ispartof | Clinical cancer research, 2000-07, Vol.6 (7), p.2868-2875 |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Antineoplastic agents Azacitidine - pharmacology Biological and medical sciences Catalytic Domain Chemotherapy DNA-Binding Proteins Gene Expression Regulation, Neoplastic - drug effects Genes, Reporter Humans Luciferases - genetics Male Medical sciences Pharmacology. Drug treatments Prostatic Neoplasms - enzymology Prostatic Neoplasms - genetics RNA Telomerase - antagonists & inhibitors Telomerase - genetics Transcription, Genetic - drug effects Transfection Tumor Cells, Cultured |
| title | Demethylating Reagent 5-Azacytidine Inhibits Telomerase Activity in Human Prostate Cancer Cells through Transcriptional Repression of hTERT |
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