PittsburghV1, Main, Exploration, bibRecord, 000917

VDR Activity is Differentially Affected by Hic-5 in Prostate Cancer and Stromal Cells

Identifieur interne : 000917 ( Main/Exploration ); précédent : 000916; suivant : 000918

VDR Activity is Differentially Affected by Hic-5 in Prostate Cancer and Stromal Cells

Auteurs : Joshua D. Solomon [États-Unis] ; Marjet D. Heitzer [États-Unis] ; Teresa T. Liu [États-Unis] ; Jan H. Beumer [États-Unis] ; Robert A. Parise [États-Unis] ; Daniel P. Normolle [États-Unis] ; Damien A. Leach [Australie] ; Grant Buchanan [Australie] ; Donald B. Defranco [États-Unis]

Source :

Molecular cancer research : MCR [ 1541-7786 ] ; 2014.

RBID : PMC:4134986

Descripteurs français

English descriptors

KwdEn :
- Androgens (genetics), Androgens (metabolism), Androgens (pharmacology), Cell Line, Tumor, Cholecalciferol (analogs & derivatives), Cholecalciferol (genetics), Cholecalciferol (metabolism), DNA-Binding Proteins (genetics), DNA-Binding Proteins (metabolism), Humans, Male, Prostatic Neoplasms (drug therapy), Prostatic Neoplasms (genetics), Prostatic Neoplasms (metabolism), Receptors, Calcitriol (genetics), Receptors, Calcitriol (metabolism), Receptors, Transforming Growth Factor beta (genetics), Receptors, Transforming Growth Factor beta (metabolism), Stromal Cells (drug effects), Stromal Cells (metabolism), Transcription Initiation Site (drug effects), Transcription, Genetic (drug effects), Transcription, Genetic (genetics), Transcriptional Activation (drug effects), Transcriptional Activation (genetics), Transforming Growth Factor beta (genetics), Transforming Growth Factor beta (metabolism), Up-Regulation (drug effects), Up-Regulation (genetics), Vitamin D3 24-Hydroxylase (genetics), Vitamin D3 24-Hydroxylase (metabolism).
MESH :
- chemical , analogs & derivatives : Cholecalciferol.
- chemical , genetics : Androgens, Cholecalciferol, DNA-Binding Proteins, Receptors, Calcitriol, Receptors, Transforming Growth Factor beta, Transforming Growth Factor beta, Vitamin D3 24-Hydroxylase.
- chemical , metabolism : Androgens, Cholecalciferol, DNA-Binding Proteins, Receptors, Calcitriol, Receptors, Transforming Growth Factor beta, Transforming Growth Factor beta, Vitamin D3 24-Hydroxylase.
- chemical , pharmacology : Androgens.
- drug effects : Stromal Cells, Transcription Initiation Site, Transcription, Genetic, Transcriptional Activation, Up-Regulation.
- drug therapy : Prostatic Neoplasms.
- genetics : Prostatic Neoplasms, Transcription, Genetic, Transcriptional Activation, Up-Regulation.
- metabolism : Prostatic Neoplasms, Stromal Cells.
- Cell Line, Tumor, Humans, Male.

Abstract

Prostate cancer patients treated with androgen deprivation therapy (ADT) eventually develop castrate-resistant prostate cancer (CRPC). 1,25-dihydroxyvitamin D3 (1,25D₃/calcitriol) is a potential adjuvant therapy that confers anti-proliferative and pro-differentiation effects in vitro, but has had mixed results in clinical trials. The impact of the tumor microenvironment on 1,25D₃ therapy in CRPC patients has not been assessed. Transforming growth factor-β (TGF-β), which is associated with the development of tumorigenic “reactive stroma” in prostate cancer, induced VDR expression in the human WPMY-1 prostate stromal cell line. Similarly, TGF-β enhanced 1,25D₃-induced up-regulation of CYP24A1, which metabolizes 1,25D₃ and thereby limits VDR activity. Ablation of Hic-5, a TGF-β-inducible nuclear receptor co-regulator, inhibited basal VDR expression, 1,25D₃-induced CYP24A1 expression and metabolism of 1,25D₃ and TGF-β-enhanced CYP24A1 expression. A Hic-5-responsive sequence was identified upstream (392-451 bp) of the CYP24A1 transcription start site that is occupied by VDR only in the presence of Hic-5. Ectopic expression of Hic-5 sensitized LNCaP prostate tumor cells to growth-inhibitory effects of 1,25D₃ independent of CYP24A1. The sensitivity of Hic-5-expressing LNCaP cells to 1,25D₃-induced growth inhibition was accentuated in co-culture with Hic-5-ablated WPMY-1 cells. Therefore, these findings indicate that the search for mechanisms to sensitize prostate cancer cells to the anti-proliferative effects of VDR ligands needs to account for the impact of VDR activity in the tumor microenvironment.

Implications

Hic-5 acts as a co-regulator with distinct effects on VDR transactivation, in prostate cancer and stromal cells, and may exert diverse effects on adjuvant therapy designed to exploit VDR activity in prostate cancer.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134986

DOI: 10.1158/1541-7786.MCR-13-0395
PubMed: 24825850
PubMed Central: 4134986

Affiliations:

Le document en format XML

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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Androgens (genetics)</term>
<term>Androgens (metabolism)</term>
<term>Androgens (pharmacology)</term>
<term>Cell Line, Tumor</term>
<term>Cholecalciferol (analogs & derivatives)</term>
<term>Cholecalciferol (genetics)</term>
<term>Cholecalciferol (metabolism)</term>
<term>DNA-Binding Proteins (genetics)</term>
<term>DNA-Binding Proteins (metabolism)</term>
<term>Humans</term>
<term>Male</term>
<term>Prostatic Neoplasms (drug therapy)</term>
<term>Prostatic Neoplasms (genetics)</term>
<term>Prostatic Neoplasms (metabolism)</term>
<term>Receptors, Calcitriol (genetics)</term>
<term>Receptors, Calcitriol (metabolism)</term>
<term>Receptors, Transforming Growth Factor beta (genetics)</term>
<term>Receptors, Transforming Growth Factor beta (metabolism)</term>
<term>Stromal Cells (drug effects)</term>
<term>Stromal Cells (metabolism)</term>
<term>Transcription Initiation Site (drug effects)</term>
<term>Transcription, Genetic (drug effects)</term>
<term>Transcription, Genetic (genetics)</term>
<term>Transcriptional Activation (drug effects)</term>
<term>Transcriptional Activation (genetics)</term>
<term>Transforming Growth Factor beta (genetics)</term>
<term>Transforming Growth Factor beta (metabolism)</term>
<term>Up-Regulation (drug effects)</term>
<term>Up-Regulation (genetics)</term>
<term>Vitamin D3 24-Hydroxylase (genetics)</term>
<term>Vitamin D3 24-Hydroxylase (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Activation de la transcription ()</term>
<term>Activation de la transcription (génétique)</term>
<term>Androgènes (génétique)</term>
<term>Androgènes (métabolisme)</term>
<term>Androgènes (pharmacologie)</term>
<term>Cellules stromales ()</term>
<term>Cellules stromales (métabolisme)</term>
<term>Cholécalciférol (analogues et dérivés)</term>
<term>Cholécalciférol (génétique)</term>
<term>Cholécalciférol (métabolisme)</term>
<term>Facteur de croissance transformant bêta (génétique)</term>
<term>Facteur de croissance transformant bêta (métabolisme)</term>
<term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Mâle</term>
<term>Protéines de liaison à l'ADN (génétique)</term>
<term>Protéines de liaison à l'ADN (métabolisme)</term>
<term>Récepteur calcitriol (génétique)</term>
<term>Récepteur calcitriol (métabolisme)</term>
<term>Récepteurs TGF-bêta (génétique)</term>
<term>Récepteurs TGF-bêta (métabolisme)</term>
<term>Régulation positive ()</term>
<term>Régulation positive (génétique)</term>
<term>Site d'initiation de la transcription ()</term>
<term>Transcription génétique ()</term>
<term>Transcription génétique (génétique)</term>
<term>Tumeurs de la prostate (génétique)</term>
<term>Tumeurs de la prostate (métabolisme)</term>
<term>Tumeurs de la prostate (traitement médicamenteux)</term>
<term>Vitamine D3 24-hydroxylase (génétique)</term>
<term>Vitamine D3 24-hydroxylase (métabolisme)</term>
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<term>Cholecalciferol</term>
<term>DNA-Binding Proteins</term>
<term>Receptors, Calcitriol</term>
<term>Receptors, Transforming Growth Factor beta</term>
<term>Transforming Growth Factor beta</term>
<term>Vitamin D3 24-Hydroxylase</term>
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<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Androgens</term>
<term>Cholecalciferol</term>
<term>DNA-Binding Proteins</term>
<term>Receptors, Calcitriol</term>
<term>Receptors, Transforming Growth Factor beta</term>
<term>Transforming Growth Factor beta</term>
<term>Vitamin D3 24-Hydroxylase</term>
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</keywords>
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<term>Transcription Initiation Site</term>
<term>Transcription, Genetic</term>
<term>Transcriptional Activation</term>
<term>Up-Regulation</term>
</keywords>
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</keywords>
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<term>Transcription, Genetic</term>
<term>Transcriptional Activation</term>
<term>Up-Regulation</term>
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<term>Androgènes</term>
<term>Cholécalciférol</term>
<term>Facteur de croissance transformant bêta</term>
<term>Protéines de liaison à l'ADN</term>
<term>Récepteur calcitriol</term>
<term>Récepteurs TGF-bêta</term>
<term>Régulation positive</term>
<term>Transcription génétique</term>
<term>Tumeurs de la prostate</term>
<term>Vitamine D3 24-hydroxylase</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Prostatic Neoplasms</term>
<term>Stromal Cells</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Androgènes</term>
<term>Cellules stromales</term>
<term>Cholécalciférol</term>
<term>Facteur de croissance transformant bêta</term>
<term>Protéines de liaison à l'ADN</term>
<term>Récepteur calcitriol</term>
<term>Récepteurs TGF-bêta</term>
<term>Tumeurs de la prostate</term>
<term>Vitamine D3 24-hydroxylase</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Androgènes</term>
</keywords>
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</keywords>
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<term>Humans</term>
<term>Male</term>
</keywords>
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<term>Cellules stromales</term>
<term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Mâle</term>
<term>Régulation positive</term>
<term>Site d'initiation de la transcription</term>
<term>Transcription génétique</term>
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</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="P1">Prostate cancer patients treated with androgen deprivation therapy (ADT) eventually develop castrate-resistant prostate cancer (CRPC). 1,25-dihydroxyvitamin D3 (1,25D<sub>3</sub>
/calcitriol) is a potential adjuvant therapy that confers anti-proliferative and pro-differentiation effects in vitro, but has had mixed results in clinical trials. The impact of the tumor microenvironment on 1,25D<sub>3</sub>
 therapy in CRPC patients has not been assessed. Transforming growth factor-β (TGF-β), which is associated with the development of tumorigenic “reactive stroma” in prostate cancer, induced VDR expression in the human WPMY-1 prostate stromal cell line. Similarly, TGF-β enhanced 1,25D<sub>3</sub>
-induced up-regulation of CYP24A1, which metabolizes 1,25D<sub>3</sub>
 and thereby limits VDR activity. Ablation of Hic-5, a TGF-β-inducible nuclear receptor co-regulator, inhibited basal VDR expression, 1,25D<sub>3</sub>
-induced CYP24A1 expression and metabolism of 1,25D<sub>3</sub>
 and TGF-β-enhanced CYP24A1 expression. A Hic-5-responsive sequence was identified upstream (392-451 bp) of the CYP24A1 transcription start site that is occupied by VDR only in the presence of Hic-5. Ectopic expression of Hic-5 sensitized LNCaP prostate tumor cells to growth-inhibitory effects of 1,25D<sub>3</sub>
 independent of CYP24A1. The sensitivity of Hic-5-expressing LNCaP cells to 1,25D<sub>3</sub>
-induced growth inhibition was accentuated in co-culture with Hic-5-ablated WPMY-1 cells. Therefore, these findings indicate that the search for mechanisms to sensitize prostate cancer cells to the anti-proliferative effects of VDR ligands needs to account for the impact of VDR activity in the tumor microenvironment.</p>
<sec id="S1"><title>Implications</title>
<p id="P2">Hic-5 acts as a co-regulator with distinct effects on VDR transactivation, in prostate cancer and stromal cells, and may exert diverse effects on adjuvant therapy designed to exploit VDR activity in prostate cancer.</p>
</sec>
</div>
</front>
</TEI>
<affiliations><list><country><li>Australie</li>
<li>États-Unis</li>
</country>
<region><li>Pennsylvanie</li>
</region>
</list>
<tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Solomon, Joshua D" sort="Solomon, Joshua D" uniqKey="Solomon J" first="Joshua D" last="Solomon">Joshua D. Solomon</name>
</region>
<name sortKey="Beumer, Jan H" sort="Beumer, Jan H" uniqKey="Beumer J" first="Jan H" last="Beumer">Jan H. Beumer</name>
<name sortKey="Defranco, Donald B" sort="Defranco, Donald B" uniqKey="Defranco D" first="Donald B" last="Defranco">Donald B. Defranco</name>
<name sortKey="Defranco, Donald B" sort="Defranco, Donald B" uniqKey="Defranco D" first="Donald B" last="Defranco">Donald B. Defranco</name>
<name sortKey="Heitzer, Marjet D" sort="Heitzer, Marjet D" uniqKey="Heitzer M" first="Marjet D" last="Heitzer">Marjet D. Heitzer</name>
<name sortKey="Liu, Teresa T" sort="Liu, Teresa T" uniqKey="Liu T" first="Teresa T" last="Liu">Teresa T. Liu</name>
<name sortKey="Normolle, Daniel P" sort="Normolle, Daniel P" uniqKey="Normolle D" first="Daniel P" last="Normolle">Daniel P. Normolle</name>
<name sortKey="Parise, Robert A" sort="Parise, Robert A" uniqKey="Parise R" first="Robert A" last="Parise">Robert A. Parise</name>
</country>
<country name="Australie"><noRegion><name sortKey="Leach, Damien A" sort="Leach, Damien A" uniqKey="Leach D" first="Damien A" last="Leach">Damien A. Leach</name>
</noRegion>
<name sortKey="Buchanan, Grant" sort="Buchanan, Grant" uniqKey="Buchanan G" first="Grant" last="Buchanan">Grant Buchanan</name>
</country>
</tree>
</affiliations>
</record>

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VDR Activity is Differentially Affected by Hic-5 in Prostate Cancer and Stromal Cells

VDR Activity is Differentially Affected by Hic-5 in Prostate Cancer and Stromal Cells

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